Substituted N-phenyl-bipyrrolidine carboxamides and therapeutic use thereof

ABSTRACT

The present invention discloses and claims a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I). 
                         
Wherein R, R 1 , R 2 , R 3  and R 4  are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this invention also discloses methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International application No.PCT/US2008/079760, filed Oct. 14, 2008, which is incorporated herein byreference in its entirety; which claims the benefit of U.S. ProvisionalApplication No. 60/980,601, filed Oct. 17, 2007.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a series of substitutedN-phenyl-bipyrrolidine carboxamides. The compounds of this invention aremodulators of H3 receptors and are, therefore, useful as pharmaceuticalagents, especially in the treatment and/or prevention of a variety ofdiseases modulated by H3 receptors including diseases associated withthe central nervous system. Additionally, this invention also relates tomethods of preparation of substituted N-phenyl-bipyrrolidinecarboxamides and intermediates therefor.

2. Description of the Art

Histamine is a ubiquitous messenger molecule released from mast cells,enterochromaffin-like cells, and neurons. The physiological actions ofhistamine are mediated by four pharmacologically defined receptors (H1,H2, H3 and H4). All histamine receptors exhibit seven transmembranedomains and are members of the G-protein-coupled receptor superfamily(GPCRs).

The H1 receptor was the first member of the histamine receptor family tobe pharmacologically defined, with the development of classicalantihistamines (antagonists), such as diphenhydramine and fexofenadine.While antagonism of the H1 receptor of the immune system is commonlyused for the treatment of allergic reactions, the H1 receptor is alsoexpressed in various peripheral tissues and the central nervous system(CNS). In the brain, H1 is involved in the control of wakefulness, mood,appetite and hormone secretion.

The H2 receptor is also expressed in the CNS, where it may modulateseveral processes, including cognition. However, H2 receptor antagonistshave primarily been developed to ameliorate gastric ulcers by inhibitinghistamine-mediated gastric acid secretion by parietal cells. Classic H2antagonists include cimetidine, ranitidine, and famotidine.

It should further be noted that H4 receptor function remains poorlydefined, but may involve immune regulation and inflammatory processes.

H3 receptors have also been pharmacologically identified in the CNS,heart, lung, and stomach. The H3 receptor differs significantly fromother histamine receptors, exhibiting low sequence homology (H1: 22%,H2: 21%, H4: 35%). H3 is a presynaptic autoreceptor on histamine neuronsin the brain and a presynaptic heteroreceptor in nonhistamine-containingneurons in both the central and peripheral nervous systems. In additionto histamine, H3 also modulates the release and/or synthesis of otherneurotransmitters, including acetylcholine, dopamine, norepinepherin andserotonin. Of particular note, presynaptic modulation of histaminerelease by H3 allows significant regulation of H1 and H2 receptors inthe brain. Modulating multiple neurotransmitter signaling pathways, H3may contribute to varied physiological processes. Indeed, extensivepreclinical evidence indicates that H3 plays a role in cognition,sleep-wake cycle and energy homeostasis.

Modulators of H3 function may be useful in the treatment of obesity andcentral nervous system disorders (Schizophrenia, Alzheimer's disease,attention-deficit hyperactivity disorder, Parkinson's disease,depression, and epilepsy), sleep disorders (narcolepsy and insomnia),cardiovascular disorders (acute myocardial infarction), respiratorydisorders (asthma), and gastrointestinal disorders. See generally,Hancock, Biochem. Pharmacol. 2006 Apr. 14; 71(8):1103-13 and Esbenshadeet al. Mol Interv. 2006 April; 6(2):77-88, 59.

Recently, compounds that are somewhat structurally related to thecompounds of the present invention have been disclosed to be melaninconcentrating hormone (MCH) receptor antagonists, see specifically U.S.Pat. No. 7,223,788. It should however be pointed out that there is nodisclosure as to the activity of the compounds disclosed therein at theH3 receptor site.

All of the references described herein are incorporated herein byreference in their entirety.

Accordingly, it is an object of this invention to provide a series ofsubstituted N-phenyl-bipyrrolidine carboxamides as selective H3 receptorligands for treatment of H3 receptor regulated CNS disorders.

It is also an object of this invention to provide processes for thepreparation of the substituted N-phenyl-bipyrrolidine carboxamides asdisclosed herein.

Other objects and further scope of the applicability of the presentinvention will become apparent from the detailed description thatfollows.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that the compounds of formula (I)are useful as H3 receptor antagonists and/or inverse agonists. Thecompounds of formula I are not specifically disclosed, nor exemplified,nor are their activity as H3 receptor antagonists/inverse agonistssuggested, in U.S. Pat. No. 7,223,788 as mentioned hereinabove.Moreover, unexpectedly it has now been found that the compounds offormula (I) are selectively active only at H3 receptors and exhibit lowactivity at the MCH-1 receptor site, which aspect becomes even moreapparent from the detailed description that follows.

Thus in accordance with the practice of this invention there is provideda compound of formula (I):

wherein

-   R, R₁, R₂ and R₃ are the same or different and independently of each    other chosen from hydrogen, (C₁-C₄)alkyl or CF₃;-   R₄ is selected from the group consisting of dimethylaminomethyl,    methanesulfonylmethyl, phenoxymethyl, vinylbenzene, ethynylbenzene,    vinylpyridine, phenyl, benzofuranyl, dihydro-benzofuranyl,    oxo-tetrahydro-benzofuranyl, benzodioxolyl, oxo-chromenyl,    dihydrobenzo-dioxinyl, dioxo-tetrahydro-1H-benzo[e]diazepinyl,    imidazopyridinyl, benzotriazolyl, benzoimidazolyl,    oxo-dihydro-benzoimidazolyl, indolyl, indazolyl, naphthyridinyl,    quinolinyl, benzoimidazothiazolyl, pyridinyl, pyrimidinyl, pyrrolyl,    triazolyl, thienyl, thiazolyl, tetrahydrofuranyl or pyrrolidinyl;-   wherein said R₄ is optionally substituted one or more times with a    substituent selected from halogen, hydroxy, methyl, ethyl,    isopropyl, propoxyethyl, phenyl, benzoyl, methoxy, difluoromethoxy,    CF₃, CN, acetyl, methanesulfonyl, sulfamoyl, dimethylamino,    N-formyl-methylamino, 2-hydroxyethylamino, 2-methoxyethylamido,    benzyloxymethyl, carboxyphenoxy, pyrazolyl, 3,5-dimethyl-pyrazolyl,    imidazolyl, triazolyl, oxazolyl, pyridinyl, oxo-dihydro-pyridinyl,    pyrimidinyl-methylamino, N-acetyl-piperidinyl, morpholinyl,    morpholinylmethyl or 2-oxo-pyrrolidinyl.

This invention further includes various salts of the compounds offormula (I) including various enantiomers or diastereomers of compoundsof formula (I).

In other aspects of this invention there are also provided variouspharmaceutical compositions comprising one or more compounds of formula(I) as well as their therapeutic use in alleviating various diseaseswhich are mediated in-part and/or fully by H3 receptors.

DETAILED DESCRIPTION OF THE INVENTION

The terms as used herein have the following meanings:

As used herein, the expression “(C₁-C₆)alkyl” includes methyl and ethylgroups, and straight-chained or branched propyl, butyl, pentyl and hexylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyland tert-butyl. Derived expressions such as “(C₁-C₄)alkoxy”,“(C₁-C₄)thioalkyl” “(C₁-C₄)alkoxy(C₁-C₄)alkyl”, “hydroxy(C₁-C₄)alkyl”,“(C₁-C₄)alkylcarbonyl”, “(C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl”,“(C₁-C₄)alkoxycarbonyl”, “amino(C₁-C₄)alkyl”, “(C₁-C₄)alkylamino”,“(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkyl”,“(C₁-C₄)dialkylcarbamoyl(C₁-C₄)alkyl” “mono- ordi-(C₁-C₄)alkylamino(C₁-C₄)alkyl”, “amino(C₁-C₄)alkylcarbonyl”“diphenyl(C₁-C₄)alkyl”, “phenyl(C₁-C₄)alkyl” “phenylcarboyl(C₁-C₄)alkyl”and “phenoxy(C₁-C₄)alkyl” are to be construed accordingly.

As used herein, the expression “cycloalkyl” includes all of the knowncyclic radicals. Representative examples of “cycloalkyl” include withoutany limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like. Derived expressions such as“cycloalkoxy”, “cycloalkylalkyl”, “cycloalkylaryl”, “cycloalkylcarbonyl”are to be construed accordingly.

As used herein, the expression “(C₂-C₆)alkenyl” includes ethenyl andstraight-chained or branched propenyl, butenyl, pentenyl and hexenylgroups. Similarly, the expression “(C₂-C₆)alkynyl” includes ethynyl andpropynyl, and straight-chained or branched butynyl, pentynyl and hexynylgroups.

As used herein the expression “(C₁-C₄)acyl” shall have the same meaningas “(C₁-C₆)alkanoyl”, which can also be represented structurally as“R—CO—,” where R is a (C₁-C₃)alkyl as defined herein. Additionally,“(C₁-C₃)alkylcarbonyl” shall mean same as (C₁-C₄)acyl. Specifically,“(C₁-C₄)acyl” shall mean formyl, acetyl or ethanoyl, propanoyl,n-butanoyl, etc. Derived expressions such as “(C₁-C₄)acyloxy” and“(C₁-C₄)acyloxyalkyl” are to be construed accordingly.

As used herein, the expression “(C₁-C₆)perfluoroalkyl” means that all ofthe hydrogen atoms in said alkyl group are replaced with fluorine atoms.Illustrative examples include trifluoromethyl and pentafluoroethyl, andstraight-chained or branched heptafluoropropyl, nonafluorobutyl,undecafluoropentyl and tridecafluorohexyl groups. Derived expression,“(C₁-C₆)perfluoroalkoxy”, is to be construed accordingly.

As used herein, the expression “(C₆-C₁₀)aryl” means substituted orunsubstituted phenyl or naphthyl. Specific examples of substitutedphenyl or naphthyl include o-, p-, m-tolyl, 1,2-, 1,3-, 1,4-xylyl,1-methylnaphthyl, 2-methylnaphthyl, etc. “Substituted phenyl” or“substituted naphthyl” also include any of the possible substituents asfurther defined herein or one known in the art. Derived expression,“(C₆-C₁₀)arylsulfonyl,” is to be construed accordingly.

As used herein, the expression “(C₆-C₁₀)aryl(C₁-C₄)alkyl” means that the(C₆-C₁₀)aryl as defined herein is further attached to (C₁-C₄)alkyl asdefined herein. Representative examples include benzyl, phenylethyl,2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.

As used herein, the expression “heteroaryl” includes all of the knownheteroatom containing aromatic radicals. Representative 5-memberedheteroaryl radicals include furanyl, thienyl or thiophenyl, pyrrolyl,isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl,and the like. Representative 6-membered heteroaryl radicals includepyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the likeradicals. Representative examples of bicyclic heteroaryl radicalsinclude, benzofuranyl, benzothiophenyl, indolyl, quinolinyl,isoquinolinyl, cinnolyl, benzimidazolyl, indazolyl, pyridofuranyl,pyridothienyl, and the like radicals.

As used herein, the expression “heterocycle” includes all of the knownreduced heteroatom containing cyclic radicals. Representative 5-memberedheterocycle radicals include tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolidinyl, 2-thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl,and the like. Representative 6-membered heterocycle radicals includepiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.Various other heterocycle radicals include, without limitation,aziridinyl, azepanyl, diazepanyl, diazabicyclo[2.2.1]hept-2-yl, andtriazocanyl, and the like.

“Halogen” or “halo” means chloro, fluoro, bromo, and iodo.

As used herein, “patient” means a warm blooded animal, such as forexample rat, mice, dogs, cats, guinea pigs, and primates such as humans.

As used herein, the expression “pharmaceutically acceptable carrier”means a non-toxic solvent, dispersant, excipient, adjuvant, or othermaterial which is mixed with the compound of the present invention inorder to permit the formation of a pharmaceutical composition, i.e., adosage form capable of administration to the patient. One example ofsuch a carrier is pharmaceutically acceptable oil typically used forparenteral administration.

The term “pharmaceutically acceptable salts” as used herein means thatthe salts of the compounds of the present invention can be used inmedicinal preparations. Other salts may, however, be useful in thepreparation of the compounds according to the invention or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, hydrobromic acid, nitricacid, sulfamic acid, sulfuric acid, methanesulfonic acid,2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid,maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinicacid, glutaric acid, acetic acid, propionic acid, salicylic acid,cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylaceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolicacid, lactic acid, pyruvic acid, malonic acid, carbonic acid orphosphoric acid. The acid metal salts such as sodium monohydrogenorthophosphate and potassium hydrogen sulfate can also be formed. Also,the salts so formed may present either as mono- or di-acid salts and canexist substantially anhydrous or can be hydrated. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include alkali metalsalts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g.calcium or magnesium salts, and salts formed with suitable organicligands, e.g. quaternary ammonium salts.

As used herein, the term “prodrug” shall have the generally acceptedmeaning in the art. One such definition includes a pharmacologicallyinactive chemical entity that when metabolized or chemically transformedby a biological system such as a mammalian system is converted into apharmacologically active substance.

The expression “stereoisomers” is a general term used for all isomers ofthe individual molecules that differ only in the orientation of theiratoms in space. Typically it includes mirror image isomers that areusually formed due to at least one asymmetric center, (enantiomers).Where the compounds according to the invention possess two or moreasymmetric centers, they may additionally exist as diastereoisomers,also certain individual molecules may exist as geometric isomers(cis/trans). Similarly, certain compounds of this invention may exist ina mixture of two or more structurally distinct forms that are in rapidequilibrium, commonly known as tautomers. Representative examples oftautomers include keto-enol tautomers, phenol-keto tautomers,nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

As used herein, ‘R’ and ‘S’ are used as commonly used terms in organicchemistry to denote specific configuration of a chiral center. The term‘R’ (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term‘S’ (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon sequence rules wherein prioritizationis first based on atomic number (in order of decreasing atomic number).A listing and discussion of priorities is contained in Stereochemistryof Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N.Mander, editors, Wiley-Interscience, John Wiley & Sons, Inc., New York,1994.

In addition to the (R)-(S) system, the older D-L system may also be usedherein to denote absolute configuration, especially with reference toamino acids. In this system a Fischer projection formula is oriented sothat the number 1 carbon of the main chain is at the top. The prefix ‘D’is used to represent the absolute configuration of the isomer in whichthe functional (determining) group is on the right side of the carbon atthe chiral center and ‘L’, that of the isomer in which it is on theleft.

The term “solvate” as used herein means that an aggregate that consistsof a solute ion or molecule with one or more solvent molecules.Similarly, a “hydrate” means that a solute ion or molecule with one ormore water molecules.

In a broad sense, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a few of the specificembodiments as disclosed herein, the term “substituted” meanssubstituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)perfluoroalkyl, phenyl, hydroxy, —CO₂H, an ester, an amide,(C₁-C₆)alkoxy, (C₁-C₆)thioalkyl, (C₁-C₆)perfluoroalkoxy, —NH₂, Cl, Br,I, F, —NH-lower alkyl, and —N(lower alkyl)₂. However, any of the othersuitable substituents known to one skilled in the art can also be usedin these embodiments.

“Therapeutically effective amount” means an amount of the compound whichis effective in treating the named disease, disorder or condition.

The term “treating” refers to:

-   -   (i) preventing a disease, disorder or condition from occurring        in a patient that may be predisposed to the disease, disorder        and/or condition, but has not yet been diagnosed as having it;    -   (ii) inhibiting the disease, disorder or condition, i.e.,        arresting its development; and    -   (iii) relieving the disease, disorder or condition, i.e.,        causing regression of the disease, disorder and/or condition.

Thus, in accordance with the practice of this invention there isprovided a compound of the formula I:

wherein

-   R, R₁, R₂ and R₃ are the same or different and independently of each    other chosen from hydrogen, (C₁-C₄)alkyl or CF₃;-   R₄ is selected from the group consisting of dimethylaminomethyl,    methanesulfonylmethyl, phenoxymethyl, vinylbenzene, ethynylbenzene,    vinylpyridine, phenyl, benzofuranyl, dihydro-benzofuranyl,    oxo-tetrahydro-benzofuranyl, benzodioxolyl, oxo-chromenyl,    dihydrobenzo-dioxinyl, dioxo-tetrahydro-1H-benzo[e]diazepinyl,    imidazopyridinyl, benzotriazolyl, benzoimidazolyl,    oxo-dihydro-benzoimidazolyl, indolyl, indazolyl, naphthyridinyl,    quinolinyl, benzoimidazothiazolyl, pyridinyl, pyrimidinyl, pyrrolyl,    triazolyl, thienyl, thiazolyl, tetrahydrofuranyl or pyrrolidinyl;-   wherein said R₄ is optionally substituted one or more times with a    substituent selected from halogen, hydroxy, methyl, ethyl,    isopropyl, propoxyethyl, phenyl, benzoyl, methoxy, difluoromethoxy,    CF₃, CN, acetyl, methanesulfonyl, sulfamoyl, dimethylamino,    N-formyl-methylamino, 2-hydroxyethylamino, 2-methoxyethylamido,    benzyloxymethyl, carboxyphenoxy, pyrazolyl, 3,5-dimethyl-pyrazolyl,    imidazolyl, triazolyl, oxazolyl, pyridinyl, oxo-dihydro-pyridinyl,    pyrimidinyl-methylamino, N-acetyl-piperidinyl, morpholinyl,    morpholinylmethyl or 2-oxo-pyrrolidinyl.

This invention further includes various salts of the compounds offormula (I) including various enantiomers or diastereomers of compoundsof formula (I). As noted hereinabove and by way of specific exampleshereafter all of the salts that can be formed including pharmaceuticallyacceptable salts are part of this invention. As also noted hereinaboveand hereafter all of the conceivable enantiomeric and diastereomericforms of compounds of formula (I) are part of this invention.

In one of the embodiments, there is disclosed hereinbelow by way ofspecific examples the compounds of formula (I) of this invention whereinR is methyl; R₂ is methyl or CF₃; and R₁ and R₃ are hydrogen.

In another embodiment, there is disclosed, the compound of formula (I)wherein R is methyl; R₁ is methyl or CF₃; and R₂ and R₃ are hydrogen.

In yet another embodiment there is disclosed compounds of formula (I) ofthis invention wherein R₄ is phenyl or phenyl substituted with one ormore groups selected from fluorine, chlorine, methyl, isopropyl,propoxyethyl, CF₃, CN, methoxy, difluoromethoxy, methanesulfonyl,sulfamoyl, dimethylamino, N-formyl-methylamino, carboxyphenoxy,oxo-dihydro-pyridinyl, pyrimidinyl-methylamino, pyrazolyl,3,5-dimethyl-pyrazolyl, imidazolyl, triazolyl, oxazolyl,N-acetyl-piperidinyl, morpholinylmethyl or 2-oxo-pyrrolidinyl.

In a further embodiment of this invention there is also disclosedcompounds of formula (I) wherein R₄ is selected from benzofuranyl,dihydro-benzofuranyl, oxo-tetrahydro-benzofuranyl, benzodioxolyl,dihydrobenzo-dioxinyl, dioxo-tetrahydro-1H-benzo[e]diazepinyl oroxo-chromenyl, in which said R₄ is optionally substituted one or moretimes with chlorine, methyl or methoxy.

In yet another embodiment of this invention there is disclosed compoundsof formula (I) wherein R₄ is selected from dimethylaminomethyl,methanesulfonylmethyl, phenoxymethyl, vinylbenzene, ethynylbenzene orvinylpyridine, in which said R₄ is optionally substituted one or moretimes with fluorine.

In yet another embodiment of this invention there is provided compoundsof formula (I) wherein R₄ is pyridinyl or pyrimidinyl, which isoptionally substituted one or more times with chlorine, methyl,2-hydroxyethylamino, 2-methoxyethylamido, benzyloxymethyl ormorpholinyl.

In a further embodiment of this invention there is also providedcompounds of formula (I) wherein R₄ is selected from imidazopyridinyl,benzotriazolyl, benzoimidazolyl, oxo-dihydro-benzoimidazolyl, indolyl,indazolyl, naphthyridinyl, quinolinyl or benzoimidazothiazolyl, in whichsaid R₄ is optionally substituted one or more times with fluorine,chlorine, hydroxy, methyl, isopropyl, methoxy or pyridinyl.

In another embodiment of this invention there is provided compounds offormula (I) wherein R₄ is selected from pyrrolyl, triazolyl, thienyl orthiazolyl, in which said R₄ is optionally substituted one or more timeswith methyl, phenyl, benzoyl or pyridinyl.

In a further embodiment of this invention there is disclosed compoundsof formula (I) wherein R₄ is selected from tetrahydrofuranyl orpyrrolidinyl, which is optionally substituted one or more times withacetyl.

It should further be noted that all of the above compounds of variousembodiments of this invention may also include corresponding saltswherever possible including the pharmaceutically acceptable saltsthereof.

In another aspect of this invention the compound of this invention maybe represented by a specific stereoisomeric form of formula (II):

wherein R, R₁, R₂, R₃ and R₄ are as defined hereinabove.

In one aspect of the invention a few of the specific compoundsencompassed by the generic scope of the invention without any limitationare enumerated as follows:

-   N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2-phenoxy-acetamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2-phenoxy-acetamide;-   N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2-phenoxy-acetamide;-   N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2-phenoxy-acetamide;-   2-dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-acetamide;-   2-methanesulfonyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetamide;-   2-methanesulfonyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetamide;-   2-methanesulfonyl-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetamide;-   2-methanesulfonyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-acetamide;-   (E)-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-pyridin-3-yl-acrylamide;-   (E)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-pyridin-3-yl-acrylamide;-   (E)-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-yl-acrylamide;-   (E)-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-3-pyridin-3-yl-acrylamide;-   (E)-3-(3-fluoro-phenyl)-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acrylamide;-   (E)-3-(3-fluoro-phenyl)-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acrylamide;-   3-phenyl-propynoic acid    [3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2-fluoro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   2-fluoro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   2-fluoro-N-[2-methyl-4-(2-(2R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   2-fluoro-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   2-fluoro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   3-fluoro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3-fluoro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3-fluoro-N-[2-methyl-4-(2-(S)-methyl-[1,3′    (S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3-fluoro-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3-fluoro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   4-fluoro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-fluoro-N-[2-methyl-4-(2-(2R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-fluoro-N-[2-methyl-4-(2(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   5-fluoro-2-methyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   5-fluoro-2-methyl-N-[2-methyl-4-(2-(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   5-fluoro-2-methyl-N-[2-methyl-4-(2(2S)-methyl-[1,3′(3′R)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   5-fluoro-2-methyl-N-[2-methyl-4-(2(2R)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   5-fluoro-2-methyl-N-[2-methyl-4-(2-(R)-methyl-[1,3′(R)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   5-fluoro-2-methyl-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   5-fluoro-2-methyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   4-chloro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-chloro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-chloro-N-[2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-chloro-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3,5-dichloro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3,5-dichloro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3,5-dichloro-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3,5-dichloro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   2,4-dimethyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   2,4-dimethyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   2,4-dimethyl-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   2,4-dimethyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   3-methanesulfonyl-4-methyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-methanesulfonyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   4-isopropyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-sulfamoyl-benzamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-(1-propoxy-ethyl)-benzamide;-   3-methoxy-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3-methoxy-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3-methoxy-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   4-methoxy-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-methoxy-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-methoxy-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-trifluoromethyl-benzamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-trifluoromethyl-benzamide;-   N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-trifluoromethyl-benzamide;-   4-difluoromethoxy-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-methanesulfonyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-methanesulfonyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-methanesulfonyl-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-cyano-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-cyano-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-cyano-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   2-dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   2-dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   3-dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3-dimethylamino-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   3-dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide;-   4-dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-dimethylamino-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-(formyl-methyl-amino)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-{4-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylcarbamoyl]-phenoxy}-benzoic    acid;-   4-imidazol-1-yl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-(1H-pyrazol-3-yl)-benzamide;-   4-(3,5-dimethyl-1H-pyrazol-4-yl)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-oxazol-5-yl-benzamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-[1,2,4]triazol-1-yl-benzamide;-   4-(4,6-dimethyl-pyrimidin-2-ylamino)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   4-[(4,6-dimethyl-pyrimidin-2-yl)-methyl-amino]-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;-   4-(1-acetyl-piperidin-3-yl)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-morpholin-4-ylmethyl-benzamide;-   N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-morpholin-4-ylmethyl-benzamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-(2-oxo-pyrrolidin-1-yl)-benzamide;-   benzo[1,3]dioxole-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl-phenyl]-amide;-   2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   benzofuran-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   benzofuran-6-carboxylic acid    [2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   5-methoxy-benzofuran-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   6-methoxy-benzofuran-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2,3-dihydro-benzofuran-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2,3-dihydro-benzofuran-5-carboxylic acid    [2-methyl-4-(2(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   4-oxo-4,5,6,7-tetrahydro-benzofuran-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic    acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1-isopropyl-1H-benzotriazole-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   6-chloro-imidazo[1,2-a]pyridine-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   imidazo[1,2-a]pyridine-8-carboxylic acid    [4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   imidazo[1,2-a]pyridine-8-carboxylic acid    [3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   imidazo[1,2-a]pyridine-8-carboxylic acid    [4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-amide;-   2-methyl-1H-benzoimidazole-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2-pyridin-3-yl-1H-benzoimidazole-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1H-indole-2-carboxylic acid    [4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1H-indole-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1H-indole-2-carboxylic acid    [3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   5-methoxy-1H-indole-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1H-Indole-5-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1H-indole-5-carboxylic acid    [2-methyl-4-(2(S)-methyl-[1,3′(S)]-bipyrrolidinyl-1′-yl-phenyl]-amide;-   1H-indole-6-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1H-indole-6-carboxylic acid    [2-methyl-4-(2(S)-methyl-[1,3′(S)]-bipyrrolidinyl-1′-yl)-phenyl]-amide;-   6-methoxy-1H-indazole-3-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   quinoline-3-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   6-fluoro-2-methyl-quinoline-3-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   [1,6]naphthyridine-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   6-chloro-4-oxo-4H-chromene-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   6-methyl-4-oxo-4H-chromene-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   benzo[d]imidazo[2,1-b]thiazole-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamide;-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamide;-   N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamide;-   N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-nicotinamide;-   6-methyl-pyridine-2-carboxylic acid    [2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   5-chloro-6-(2-hydroxy-ethylamino)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamide;-   6-benzyloxymethyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamide;-   pyridine-2,5-dicarboxylic acid    2-[(2-methoxy-ethyl)-amide]5-{[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide};-   N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-6-morpholin-4-yl-nicotinamide;-   4-benzoyl-1H-pyrrole-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   thiophene-2-carboxylic acid    [4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   thiophene-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   thiophene-2-carboxylic acid    [3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2-pyridin-3-yl-thiazole-4-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   2-pyridin-4-yl-thiazole-4-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   tetrahydro-furan-2-carboxylic acid    [2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1-acetyl-pyrrolidine-2-carboxylic acid    [4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;-   1-acetyl-pyrrolidine-2-carboxylic acid    [3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide; and-   1-acetyl-pyrrolidine-2-carboxylic acid    [2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide;

Again all of the conceivable salts of the above noted compoundsincluding the pharmaceutically acceptable salts are part of thisinvention.

The compounds of this invention can be synthesized by any of theprocedures known to one skilled in the art. Specifically, several of thestarting materials used in the preparation of the compounds of thisinvention are known or are themselves commercially available. Thecompounds of this invention and several of the precursor compounds mayalso be prepared by methods used to prepare similar compounds asreported in the literature and as further described herein. Forinstance, as stated hereinabove a few of the structurally similarcompounds have been disclosed in U.S. Pat. No. 7,223,788. Also, see R.C. Larock, “Comprehensive Organic Transformations,” VCH publishers,1989.

It is also well known that in various organic reactions it may benecessary to protect reactive functional groups, such as for example,amino groups, to avoid their unwanted participation in the reactions.Conventional protecting groups may be used in accordance with standardpractice and known to one of skilled in the art, for example, see T. W.Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”John Wiley and Sons, Inc., 1991. For example, suitable amine protectinggroups include without any limitation sulfonyl (e.g., tosyl), acyl(e.g., benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g.,benzyl), which may be removed subsequently by hydrolysis orhydrogenation as appropriate. Other suitable amine protecting groupsinclude trifluoroacetyl [—C(═O)CF₃] which may be removed by basecatalyzed hydrolysis, or a solid phase resin bound benzyl group, such asa Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) or a2,6-dimethoxy-4-[2-(polystyrylmethoxy)ethoxy]benzyl, which may beremoved by acid catalyzed hydrolysis, for example with TFA.

More specifically, the compounds disclosed herein and various precursorsused therefor can be synthesized according to the following proceduresof Schemes 1-4, wherein R, R₁, R₂, R₃ and R₄ are as defined for FormulaI unless otherwise indicated.

For instance, Scheme 1 illustrates the preparation of the intermediate[1,3′]-pyrrolidinyl-pyrrolidine of formula (4), wherein R is as definedherein. First, in step 1, Scheme 1, suitably protected (for exampletert-butyloxycarbonyl (boc)) pyrrolidinone of formula (1) is condensedwith a desired substituted pyrrolidine of formula (2) by any of theknown reductive amination procedures to from an intermediate of formula(3). For instance, such condensation reactions are generally carried outin the presence of reducing agents such as triacetoxyborohydride in aninert atmosphere, such as nitrogen atmosphere. The reaction can becarried out either at sub-ambient, ambient or super-ambient reactiontemperatures and pressures. Typically, such reactions are carried out atroom temperature at atmospheric pressure of nitrogen. The reactionmixture is then worked-up using procedures known to one skilled in theart to isolate the intermediate of formula (3).

In step 2, Scheme 1, the intermediate (3) is then de-protected to formthe desired [1,3′]pyrrolidinyl-pyrrolidine of formula (4). Suchdeprotection reactions are generally carried out under acidicconditions, for example, in the presence of hydrochloric acid atsub-ambient to ambient temperatures, for example in the temperaturerange of about −10° C. to room temperature. However, other suitablereaction temperatures can also be used depending upon the nature of theintermediate of formula (3).

Scheme 2 illustrates preparation of enantiomerically pure isomers of the[1,3′]-pyrrolidinyl-pyrrolidine of formula (9), wherein R is as definedherein. In step 1, Scheme 2, suitably protected (for example boc)pyrrolidine alcohol of formula (5) is treated with p-toluene sulfonylchloride to form intermediate of formula (6). This reaction can becarried out using any of the procedures known to one skilled in the art,such as for example carrying out the reaction in the presence of asuitable base such as triethylamine and DMAP in a suitable organicsolvent, preferably an aprotic solvent such as dichloromethane atsub-ambient or ambient temperature conditions.

In step 2, Scheme 2, the intermediate of formula (6) is condensed with adesired pyrrolidine of formula (7). Again, such condensation reactionscan be carried out using any of the procedures known to one skilled inthe art in order to obtain the intermediate of formula (8). Typically,such condensation reactions are carried out in the presence of a basesuch as potassium carbonate in the presence of solvents such asacetonitrile at ambient to super-ambient temperature conditions.

In step 3, Scheme 2, the intermediate of formula (8) is then reactedwith an acid, such as hydrochloric acid in a suitable solvent, such asdioxane, to form the desired stereospecific isomer of[1,3′]-pyrrolidinyl-pyrrolidine intermediate of formula (9). It has nowbeen found that the intermediates of formula (9) can be readily formedin accordance with the process of this invention with high enantiomericpurity, specific details of which are provided hereinbelow by way ofvarious examples. In general, the enantiomeric purity can be determinedby chiral HPLC.

Scheme 3 illustrates the preparation ofamino-phenyl-pyrrolidinyl-pyrrolidine intermediate of formula (12),wherein R, R₁ and R₂ are as defined herein. In step 1, Scheme 3,suitably substituted nitrobenzene of formula (10), wherein X is asuitable leaving group, such as Cl, F, Br, or triflate (OTf) iscondensed with the [1,3′]-pyrrolidinyl-pyrrolidine of formula (4) inorder to form an intermediate of formula (11). Such condensationreactions can again be carried out using any of the procedures known toone skilled in the art. For example, such condensation reaction can becarried out in a polar solvent such as DMSO in the presence of a basesuch as potassium carbonate at ambient to super-ambient temperatureconditions.

In step 2, Scheme 3, intermediate of formula (11) is reduced byhydrogenation or other known chemical methods, such as using tindichloride in hydrochloric acid, to form the key intermediate (12).

Scheme 4 illustrates the preparation of compounds of formula (I) of thisinvention using either Method A or Method B depending upon theavailability of desired carboxylic acid of formula R₄—CO₂H either in theform of the acid itself or its acid chloride, wherein R, R₁, R₂ and R₄are as described herein and R₃ is hydrogen.

In Method A, Scheme 4 the acid chloride of formula (13) can be reactedwith the intermediate (12) using any of the conditions known to oneskilled in the art. Typically, such conditions include without anylimitations reaction of the acid chloride with the intermediate offormula (12) in a suitable organic solvent such as for exampledichloromethane in the presence of a suitable base such as pyridine.Such reactions are generally carried out at sub-ambient temperatureconditions, for example around 0° C., however ambient to super-ambienttemperature conditions may also be suitable in certain situationsdepending upon the nature of the acid chloride and the intermediate(12).

Similarly, in Method B, Scheme 4, the carboxylic acid of formula (14)can be reacted with the intermediate of formula (12) under variousreaction conditions known to one skilled in the art. For instance, theacid of formula (14) is reacted with intermediate of formula (12) atsub-ambient temperature conditions in the presence of suitable reagentssuch as for example a mixture of N-methylmorpholine,1-hydroxybenzotriazole and EDC.

As already noted hereinabove, the compounds of this invention canreadily be converted into salts. More particularly, the compounds of thepresent invention are basic, and as such compounds of this invention areuseful in the form of the free base or in the form of a pharmaceuticallyacceptable acid addition salt thereof. Acid addition salts may be a moreconvenient form for use; and, in practice, use of the salt forminherently amounts to use of the free base form. The acids which can beused to prepare the acid addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically acceptablesalts, that is, salts whose anions are non-toxic to the patient inpharmaceutical doses of the salts, so that the beneficial inhibitoryeffects inherent in the free base are not vitiated by side effectsascribable to the anions. Although pharmaceutically acceptable salts ofsaid basic compound is preferred, all acid addition salts are useful assources of the free base form even if the particular salt, per se, isdesired only as an intermediate product as, for example, when the saltis formed only for purposes of purification, and identification, or whenit is used as intermediate in preparing a pharmaceutically acceptablesalt by ion exchange procedures.

In another aspect of this embodiment, a specific disease, a disorder ora condition that can be treated with the compound of this inventioninclude, without any limitation the following: sleep-related disorders(specific examples include without any limitation narcolepsy, circadianrhythm sleep disorders, obstructive sleep apnea, periodic limb movementand restless leg syndrome, excessive sleepiness and drowsiness due tomedication side-effect, etc.), neurological disorders (specific examplesthat may be enumerated include but not limited to dementia, Alzheimer'sdisease, multiple sclerosis, epilepsy and neuropathic pain),neuropsychological and cognitive disorders (a few of the specificexamples include without any limitation include schizophrenia, attentiondeficit/hyperactivity disorder, Alzheimer's disease, depression,seasonal affective disorder, and cognitive impairment).

As described hereinbelow by way of specific examples, the compounds offormula (I) bind to the H3 receptors and demonstrate inverse agonismversus H3 functional activity. Therefore, the compounds of thisinvention may have utility in the treatment of diseases or conditionsameliorated with H3 receptor ligands. More specifically, the compoundsof the present invention are H3 receptor ligands that modulate functionof the H3 receptor by antagonizing the activity of the receptor.Further, the compounds of this invention may be inverse agonists thatinhibit the basal activity of the receptor or they may be antagoniststhat completely block the action of receptor-activating agonists.Additionally, the compounds of this invention may also be partialagonists that partially block or partially activate the H3 receptor orthey may be agonists that activate the receptor. Thus the compounds ofthis invention may act differentially as antagonists, inverse agonistsand/or partial agonists depending on functional output, histamine toneand or tissue context. Accordingly, the differential activities of thesecompounds may allow for utility to ameliorate multiple disease states asspecifically enumerated above.

Thus in one aspect of this invention there is provided a method oftreating a disease in a patient, said disease selected from the groupconsisting of sleep related disorder, dementia, Alzheimer's disease,multiple sclerosis, cognitive disorder, attention deficit hyperactivitydisorder and depression, comprising administering to said patient atherapeutically effective amount of a compound of formula (I).

One of skill in the art readily appreciates that the pathologies anddisease states expressly stated herein are not intended to be limitingrather to illustrate the efficacy of the compounds of the presentinvention. Thus it is to be understood that the compounds of thisinvention may be used to treat any disease caused by the effects of H3receptors. That is, as noted above, the compounds of the presentinvention are modulators of H3 receptors and may be effectivelyadministered to ameliorate any disease state which is mediated all or inpart by H3 receptors.

All of the various embodiments of the compounds of this invention asdisclosed herein can be used in the method of treating various diseasestates as described herein. As stated herein, the compounds used in themethod of this invention are capable of inhibiting the effects of H3receptor and thereby alleviating the effects and/or conditions causeddue to the activity of H3.

In another embodiment of the method of this invention, the compounds ofthis invention can be administered by any of the methods known in theart. Specifically, the compounds of this invention can be administeredby oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal,intraperitoneal or topical route.

Finally, in yet another embodiment of this invention, there is alsoprovided a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of formula (I), including enantiomers,stereoisomers, and tautomers of said compound and pharmaceuticallyacceptable salts, solvates or derivatives thereof, with said compoundhaving the general structure shown in formula I as described herein.

As described herein, the pharmaceutical compositions of this inventionfeature H3 inhibitory activity and thus are useful in treating anydisease, condition or a disorder caused due to the effects of H3 in apatient. Again, as described above, all of the preferred embodiments ofthe compounds of this invention as disclosed herein can be used inpreparing the pharmaceutical compositions as described herein.

Preferably the pharmaceutical compositions of this invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,sterile parenteral solutions or suspensions, metered aerosol or liquidsprays, drops, ampoules, auto-injector devices or suppositories; fororal, parenteral, intranasal, sublingual or rectal administration, orfor administration by inhalation or insufflation. Alternatively, thecompositions may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. An erodible polymercontaining the active ingredient may be envisaged. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation composition is then subdivided into unitdosage forms of the type described above containing from 0.1 to about500 mg of the active ingredient of the present invention. Flavored unitdosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50or 100 mg, of the active ingredient. The tablets or pills of the novelcomposition can be coated or otherwise compounded to provide a dosageform affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The pharmaceutical compositions of this invention can be administered byany of the methods known in the art. In general, the pharmaceuticalcompositions of this invention can be administered by oral,intramuscular, subcutaneous, rectal, intratracheal, intranasal,intraperitoneal or topical route. The preferred administrations of thepharmaceutical composition of this invention are by oral and intranasalroutes. Any of the known methods to administer pharmaceuticalcompositions by an oral or an intranasal route can be used to administerthe composition of this invention.

In the treatment of various disease states as described herein, asuitable dosage level is about 0.01 to 250 mg/kg per day, preferablyabout 0.05 to 100 mg/kg per day, and especially about 0.05 to 20 mg/kgper day. The compounds may be administered on a regimen of 1 to 4 timesper day.

This invention is further illustrated by the following examples whichare provided for illustration purposes and in no way limit the scope ofthe present invention.

Examples (General)

As used in the examples and preparations that follow, the terms usedtherein shall have the meanings indicated: “kg” refers to kilograms, “g”refers to grams, “mg” refers to milligrams, “μg” refers to micrograms,“pg” refers to picograms, “lb” refers to pounds, “oz” refers to ounces,“mol” refers to moles, “mmol” refers to millimoles, “μmole” refers tomicromoles, “nmole” refers to nanomoles, “L” refers to liters, “mL” or“ml” refers to milliliters, “μL” refers to microliters, “gal” refers togallons, “° C.” refers to degrees Celsius, “R_(f)” refers to retentionfactor, “mp” or “m.p.” refers to melting point, “dec” refers todecomposition, “bp” or “b.p.” refers to boiling point, “mm of Hg” refersto pressure in millimeters of mercury, “cm” refers to centimeters, “nm”refers to nanometers, “abs.” refers to absolute, “conc.” refers toconcentrated, “c” refers to concentration in g/mL, “DMSO” refers todimethyl sulfoxide, “DMF” refers to N,N-dimethylformamide, “cDI” refersto 1,1′-carbonyldiimidazole, “DCM” or “CH₂Cl₂” refers todichloromethane, “DCE” refers to 1,2-dichloroethane, “HCl” refers tohydrochloric acid, “EtOAc” refers to ethyl acetate, “PBS” refers toPhosphate Buffered Saline, “IBMX” refers to 3-isobutyl-1-methylxanthine,“PEG” refers to polyethylene glycol, “MeOH” refers to methanol, “MeNH₂”refers to methyl amine, “N₂” refers to nitrogen gas, “iPrOH” refers toisopropyl alcohol, “Et₂O” refers to ethyl ether, “LAH” refers to lithiumaluminum hydride, “heptane” refers to n-heptane, “HMBA-AM” resin refersto 4-hydroxymethylbenzoic acid amino methyl resin, “PdCl₂(dppf)₂” refersto 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride DCMcomplex, “HBTU” refers to2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate,“DIEA” refers to diisopropylethylamine, “CsF” refers to cesium fluoride,“Mel” refers to methyl iodide, “AcN,” “MeCN” or “CH₃CN” refers toacetonitrile, “TFA” refers to trifluoroacetic acid, “THF” refers totetrahydrofuran, “NMP” refers to 1-methyl-2-pyrrolidinone, “H₂O” refersto water, “BOC” refers to t-butyloxycarbonyl, “brine” refers to asaturated aqueous sodium chloride solution, “M” refers to molar, “mM”refers to millimolar, “μM” refers to micromolar, “nM” refers tonanomolar, “N” refers to normal, “TLC” refers to thin layerchromatography, “HPLC” refers to high performance liquid chromatography,“HRMS” refers to high resolution mass spectrum, “L.O.D.” refers to losson drying, “μCi” refers to microcuries, “i.p.” refers tointraperitoneally, “i.v.” refers to intravenously, anhyd=anhydrous;aq=aqueous; min=minute; hr=hour; d=day; sat.=saturated; s=singlet,d=doublet; t=triplet; q=quartet; m=multiplet; dd=doublet of doublets;br=broad; LC=liquid chromatograph; MS=mass spectrograph;ESI/MS=electrospray ionization/mass spectrograph; RT=retention time;M=molecular ion, “˜”=approximately.

Reactions generally are run under a nitrogen atmosphere. Solvents aredried over magnesium sulfate and are evaporated under vacuum on a rotaryevaporator. TLC analyses are performed with EM Science silica gel 60F254 plates with visualization by UV irradiation. Flash chromatographyis performed using Alltech prepacked silica gel cartridges. The ¹H NMRspectra are run at 300 MHz on a Gemini 300 or Varian Mercury 300spectrometer with an ASW 5 mm probe, and usually recorded at ambienttemperature in a deuterated solvent, such as D₂O, DMSO-D₆ or CDCl₃unless otherwise noted. Chemical shifts values (δ) are indicated inparts per million (ppm) with reference to tetramethylsilane (TMS) as theinternal standard.

High Pressure Liquid Chromatography-Mass Spectrometry (LCMS) experimentsto determine retention times (R_(T)) and associated mass ions areperformed using one of the following methods:

-   Mass Spectra (MS) are recorded using a Micromass mass spectrometer.    Generally, the method used was positive electro-spray ionization,    scanning mass m/z from 100 to 1000. Liquid chromatography was    performed on a Hewlett Packard 1100 Series Binary Pump & Degasser;    Auxiliary detectors used were: Hewlett Packard 1100 Series UV    detector, wavelength=220 nm and Sedere SEDEX 75 Evaporative Light    Scattering (ELS) detector temperature=46° C., N₂ pressure=4 bar.-   LCT: Grad (AcN+0.05% TFA):(H₂O+0.05% TFA)=5:95 (0 min) to 95:5 (2.5    min) to 95:5 (3 min). Column: YMC Jsphere 33×2 4 μM, 1 ml/min-   MUX: Column: YMC Jsphere 33×2, 1 ml/min-   Grad (AcN+0.05% TFA):(H2O+0.05% TFA)=5:95 (0 min) to 95:5 (3.4 min)    to 95:5 (4.4 min).-   LCT2: YMC Jsphere 33×2 4 μM, (AcN+0.05% TFA):(H2O+0.05% TFA)=5:95 (0    min) to 95:5 (3.4 min) to 95:5 (4.4 min)-   QU: YMC Jsphere 33×2 1 ml/min, (AcN+0.08% formic acid):(H2O+0.1%    formic acid)=5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3.0 min)

The following examples describe the procedures used for the preparationof various starting materials employed in the preparation of thecompounds of this invention.

INTERMEDIATES Intermediate (i)2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester

To a solution of N—BOC-3-pyrrolidinone (4.22 g, 22.9 mmol) and2-methylpyrrolidine (1.95 g, 22.9 mmol) (HCl salt was made by additionof 22.9 mL of 1 M HCl in ether into the DCM solution of2-methylpyrroline, then evaporated) in DCE (60 mL) was added powderedsodium triacetoxyborohydride slowly under N₂ at r.t. The yellowish milkysolution was stirred at r.t. overnight. LC/MS−m/z 255 and 199 ([M+H]⁺and [[M+H]-tBu]⁺).

The reaction was quenched with aq. NaHCO₃ solution. The two layers wereseparated, and the aqueous layer was extracted with DCM (20 mL×2). Thecombined DCM extracts were washed with sodium bicarbonate (10 mL), andbrine (5 mL×2), dried (anhydrous potassium carbonate), filtered, andconcentrated in vacuo. The crude product was purified on a silica gelcolumn, eluted with DCM and 7.5% MeOH in DCM to get the title compoundas a liquid 5.50 g (yield: 94%). MS: 255 (M+H)⁻; TLC: 0.5 (10% MeOH inDCM).

Intermediate (ii) 2-Methyl-[1,3′]bipyrrolidinyl hydrochloride

2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester(Intermediate (i) obtained above, 5.50 g, 21.62 mmol) was treated with20 mL of 4 M HCl in dioxane at 0° C. The solution was stirred undernitrogen at r.t. overnight. TLC (10% MeOH in DCM) did not detect thestarting material. N₂ was passed through the solution with stirring. Theoutlet was passed though KOH solution to absorb HCl for 30 min. Thesolvent was removed by evaporation to dryness to get the title compoundas a hygroscopic gummy material, 5.3 g (˜100%). This material was usedwithout further purification in subsequent steps as illustrated below.LCMS: R_(T)=0.35 minutes, MS: 155 (M+H)⁺.

¹H NMR (D₂O, 300 MHz): 4.30 (m), 3.85 (m), 3.76 (s), 3.5 (m), 3.46 (m),3.32 (m), 2.66 (m), 2.28 (m), 2.10 (m), 1.46 (bs).

Intermediate (iii)2-Methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′]bipyrrolidinyl

2-Methyl-[1,3′]bipyrrolidinyl hydrochloride (Intermediate (ii) obtainedabove, 5.3 g, 21.6 mmol, 1.12 equiv.) was dissolved in anhydrous DMSO(30 mL). To this solution was added 5-fluoro-2-nitrotoluene (3.00 g,18.78 mmol, 1 equiv.), followed by powdered potassium carbonate (8.9 g,65 mmol). The suspension was heated on an oil bath to 85° C. for 4 hwhen the starting material was consumed as determined by TLC (5% MeOH inDCM) and LC/MS. To the suspension were added 20 mL of water and 50 mL ofDCM. The two layers were separated, and the aqueous layer was extractedwith DCM (20 mL×2). The combined DCM extracts were washed with sodiumbicarbonate (20 mL), and brine (15 mL×2), dried (anhydrous potassiumcarbonate), filtered, and concentrated in vacuo. The crude product waspurified on a silica gel column, eluted with 5% MeOH in DCM to get thetitle compound as a yellow solid after drying, 5.47 g (100%). MS: 290(M+H⁺).

¹H NMR (300 MHz, CDCl₃): 8.10 (d, 9 Hz, 1H), 6.36 (bd, 9 Hz, 1H), 6.28(bs, 1H), 3.4-3.2 (m, 5H), 3.00-2.78 (m, 2H), 2.64 (s, 3H), 1.7-2.2 (m,6H), 1.5 (m, 1H), 1.06 (m, 3H).

Intermediate (iv) 4-(2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine

A solution of 2-methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′]bipyrrolidinyl(Intermediate (iii) obtained above, 2.23 g, 7.7 mmol) in MeOH wasde-aerated and nitrogen was introduced. To this solution was added Pd—C(10%). This mixture was stirred under H₂ atmosphere at r.t. for 8 h. TLC(10% MeOH in DCM) and LC/MS showed the reaction was complete. Themixture was passed through a Celite pad, rinsed with methanol. Thefiltrate was concentrated to dryness, and further dried under highvacuum to yield a reddish brown liquid after drying under high vacuum toobtain the title compound as a gummy black liquid, 1.73 g (86%). Thismaterial was used in the next step without further purification andstorage. MS: 260 (M+H⁺).

Intermediate (v) 2-(2R)-Methyl-[1,3′]bipyrrolidinyl hydrochloride

To a solution of N—BOC-3-pyrrolidinone (1.26 g, 6.83 mmol) and2-(R)-methylpyrroline (0.83 g, 6.83 mmol) in DCE (20 mL) was addedpowdered sodium triacetoxyborohydride slowly under N₂ at r.t. Theyellowish milky solution was stirred at r.t. overnight. LC/MS showed m/z255 and 199 (base peak and M-tBu peak).

The reaction was quenched with aqueous NaHCO₃ solution. The two layerswere separated, and the aqueous layer was extracted with DCM (10 mL×2).The combined DCM extracts were washed with sodium bicarbonate (10 mL),and brine (5 mL×2), dried (anhydrous potassium carbonate), filtered, andconcentrated in vacuo. The crude product was purified on a silica gelcolumn, eluted with DCM and 7.5% MeOH in DCM to get a liquid, 1.29 g(yield: 74%). This thick liquid as obtained above (1.29 g, 5.08 mmol)was treated with 16 mL of 4M HCl in dioxane at 0° C. The solution wasstirred under nitrogen at r.t. overnight. TLC (10% MeOH in DCM) did notdetect the starting material.

N₂ was passed through the solution with stirring. The outlet was passedthough KOH solution to absorb HCl for 30 min. The solvent was removed byevaporation to dryness to get a hygroscopic gum (HCl salt and hydrate,exact composition unknown), 1.32 g (˜100%). This material was usedwithout further purification in subsequent steps as described below.LCMS: R_(T)=0.35 minutes, MS: 155 (M+H).

Intermediate (vi)2-(2R)-Methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′]bipyrrolidinyl

5-Fluoro-2-nitrotoluene (1.55 g, 10 mmol) was dissolved in anhydrousDMSO. To this solution was added 2-(2R)-methyl-[1,3′]bipyrrolidinylhydrochloride (2.30 g, 15 mmol), followed by powdered potassiumcarbonate. The suspension was heated on an oil bath to 85° C. for 3 hwhen the starting material was consumed as determined by TLC (5%MeOH/DCM) and LC/MS. To the suspension were added 20 mL of water and 50mL of DCM. The two layers were separated, and the aqueous layer wasextracted with DCM (20 mL×2). The combined DCM extracts were washed withsodium bicarbonate (20 mL), and brine (15 mL×2), dried (anhydrouspotassium carbonate), filtered, and concentrated in vacuo. The crudeproduct was purified on a silica gel column, eluted with 5% MeOH in DCMto get the title compound as a yellow solid after drying, 2.70 g (93%).MS: 290 (M+1).

¹H NMR (CDCl₃, 300 MHz): 8.10 (d, 9 Hz,), 6.36 (bd, 9 Hz), 6.28 (bs)3.4-3.2 (m), 3.00-2.78 (m), 2.64 (s), 1.7-2.2 (m) 1.5 (m), 1.06 (d, 6.6Hz), 1.14 (d, 6.6 Hz).

Intermediate (vii)2-Methyl-4-(2-(2R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine

A solution of2-(2R)-methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′]bipyrrolidinyl (2 g,6.9 mmol) in MeOH (15 mL) was de-aerated and nitrogen was introduced. Tothis solution was added Pd—C (10%, 0.20 g). The nitrogen was replacedwith hydrogen and the mixture was stirred under H₂ atmosphere at r.t.overnight. TLC (10% MeOH in DCM) and LC/MS showed the reaction wascomplete. The mixture was passed through a celite pad, rinsed withmethanol. The filtrate was concentrated to dryness, and further driedunder high vacuum to yield the title compound as a reddish brown liquidafter drying under high vacuum, 2.02 g (100% yield). This material isused in the next step without further purification. MS: 260 (M+H⁺).

Intermediate (viii) 2-(2S)-Methyl-[1,3′]bipyrrolidinyl hydrochloride

The title compound was prepared in a manner substantially the same asintermediate (v) by condensing N—BOC-3-pyrrolidinone (1.26 g, 6.83 mmol)and 2-(S)-methylpyrroline, followed by de-protection with hydrochloridein dioxane.

LCMS: R_(T)=0.36 minutes, MS: 155 (M+H).

¹H NMR (CDCl₃, 300 MHz): 4.16 (m), 3.77 (m), 3.61 (m), 3.13, (m) 3.31(m), 2.53 (m), 2.41 (m) 1.98 (m), 1.67 (m), 1.31 (m).

Intermediate (ix)3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester

A round-bottomed flask was charged with p-toluenesulfonyl chloride(16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. Thesolution was cooled to an ice-water bath and evacuated and purged withnitrogen. To this solution was added a solution of(3R)-(−)-N—BOC-3-hydroxypyrrolidine (purchased from Aldrich) (10.47 g,55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine(16.2 mL). The solution was stirred under nitrogen overnight from 0° C.to rt. TLC (5% MeOH in DCM) showed the completion of the reaction. Thereaction was quenched by addition of polymer-supported amine (8 g),stirred 30 min. 100 mL of DCM was added. The organic layer was washedwith H₃PO₄ (1M, 2×50 mL), followed by NaHCO₃ (50 mL), brine (50 mL),dried (K₂CO₃), filtered through a silica gel pad, and concentrated toobtain the title compound as a liquid, 15.82 g (82.8%). MS: 363 (M+Na⁺);TLC (DCM) Rf=0.3.

¹H NMR (CDCl₃, 300 MHz): 7.80 (d, 9.0 Hz, 2H), 7.35 (d, 7.8 Hz, 2H),5.04 (bs, 1H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).

Intermediate (x) 2-(2S)-Methyl-[1,3′(3′S)]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester

3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester (Intermediate (ix) obtained above, 15.82 g, 46.4 mmol, 1 equiv.)and S-(+)-2-methyl-piperindine (obtained from Advanced Asymmetrics),(7.88 g, 92.79 mmol, 2 equiv.) were dissolved in anhydrous CH₃CN (150mL). To this colorless solution was added powdered K₂CO₃ (powder, 325mess, 98+%, 14.11 g, 102.08 mmol, 2.2 equiv.) at r.t. The suspension washeated in an oil bath maintained at 80° C. for 24 h. TLC (3% MeOH in DCMfor starting material (SM) and 7.5% MeOH in DCM for product) showed thatthe SM was consumed almost completely. LC/MS showed very little amountof SM at m/z 363, and the product at 255.

The suspension was concentrated to dryness. The residue was taken inwater (25 mL) and DCM (80 mL). The two layers were separated, and theaqueous layer was extracted with DCM (20 mL×2). The combined DCMextracts were washed with sodium bicarbonate (25 mL), and brine (25 mL),dried (anhydrous potassium carbonate), filtered, and concentrated invacuo. The crude product was purified on a silica gel column, elutedwith MeOH in DCM (0 to 7.5%) to get the title compound as a gummymaterial, 7.91 g (67%). LCMS: R_(T)=1.27 minutes, MS: 255 (M+H).

¹H NMR (300 MHz, CDCl₃): 3.15 (m, 2H), 3.3 (m, 3H), 2.97 (m, 1H), 2.71(m, 1H), 2.47 (m, 1H), 1.98 (m, 2H), 1.96-1.67 (m, 4H), 1.46 (s, 9H),1.06 (d, 6.2 Hz, 3H).

Intermediate (xi) 2-(2R)-Methyl-[1,3′(3′S)]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asintermediate (x) by condensing3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester (Intermediate (ix) obtained above and R-(−)-2-methylpiperindine(obtained from Advanced Asymmetrics). LCMS: R_(T)=1.05 minutes, MS: 255(M+H).

¹H NMR (300 MHz, CDCl3): 3.30 (m, 1H), 3.14 (bs, 2H), 2.91 (m, 1H), 2.75(m, 1H), 2.51 (m, 1H), 2.07-1.69 (m, 6H), 1.46 (s, 9H), 1.10 (d, 6.0 Hz,3H).

Intermediate (xii)3-(3S)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester

A round bottomed flask was charged with 80 mL of anhydrous DCM. Thesolvent was evacuated and purged with nitrogen. To this solvent wasadded (3S)-1-BOC-3-pyrrolidinol (obtained from Astatech), (16.32 g, 33.8mmol), DMAP (0.4 g). The solution was cooled to an ice-water bath. Tothis cold solution was added a solution of p-toluene-sulfonyl chloride(9.67 g, 50.87 mmol, 1.5 equiv.) in 20 mL of DCM. The ice-water bath wasremoved and the solution was stirred under nitrogen overnight. TLC (5%MeOH in DCM for SM, 12 visualization; DCM for product, UV) showed thecompletion of the reaction. The reaction was quenched by addition ofpolymer-supported amine (4.5 g), stirred 30 min. 50 mL of DCM was addedand filtered. The filtration pad was washed with DCM. The organic waswashed with H₃PO₄ (1M, 2×50 mL), followed by NaHCO₃ (50 mL, brine (50mL), dried (K₂CO₃), filtered and concentrated to a liquid. This waspurified on a 110 g silica gel column on Analogix using 0-2% MeOH in DCMto obtain pure product, 8.82 g (77% yield).

TLC (DCM) Rf=0.3. LC: Rt=3.55 min, 100% pure based on total ion, MS: 363(M+Na); 342, 327, 286 (base).

¹H NMR (300 MHz, CDCl₃): 7.81 (d, 8.7 Hz, 2H), 7.37 (d, 8.7 Hz, 2H),5.04 (bs, 1H), 3.45 (m, 4H), 2.46 (s, 3H), 1.44 (s, 9H).

Intermediate (xiii)2-(2S)-Methyl-[1,3′(3′R)]bipyrrolidinyl-1′-carboxylic acid tert-butylester

3-(3S)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester (Intermediate (xii) obtained above) (6.82 g, 19.97 mmol, 1 equiv.)and S-(+)-2-methyl-piperindine (obtained from Advanced Asymmetrics),(3.40 g, 40 mmol, 2 equiv.) were dissolved in anhydrous CH₃CN (65 mL).To this colorless solution was added powder K₂CO₃ (powder, 325 mess,98+%, 6.10 g, 44.2 mmol, 2.2 equiv.) at r.t. The suspension was heatedwith stirring under nitrogen over an oil bath maintained at 80° C. for24 h. TLC (3% MeOH in DCM for SM, 7.5% MeOH in DCM for product) showedthe SM was consumed almost completely. LC/MS showed very little amountof SM at m/z 363.

The suspension was concentrated to dryness. The residue was taken inwater (25 mL) and DCM (80 mL). The two layers were separated, and theaqueous layer was extracted with DCM (20 mL×2). The combined DCMextracts were washed with sodium bicarbonate (25 mL), and brine (25 mL),dried (anhydrous potassium carbonate), filtered, and concentrated invacuo. The crude product was purified on a silica gel column (70 g) onAnalogix, eluted with MeOH in DCM (0 to 7.5%) to obtain 4.08 g (80.3%)of the title compound as a gummy material. LCMS: R_(T)=1.14 minutes, MS:255 (M+H).

¹H NMR (300 MHz, CDCl₃): 3.30 (m, 1H), 3.14 (bs, 2H), 2.91 (m, 1H), 2.75(m, 1H), 2.51 (m, 1H), 2.07-1.69 (m, 6H), 1.46 (s, 9H), 1.10 (d, 6.0 Hz,3H).

Intermediate (xiv) 2-(2R)-Methyl-[1,3′(3′R)]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asintermediate (xiii) by condensing3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester (Intermediate (xiii) obtained above) and R-(−)-2-methylpiperindine(obtained from Advanced Asymmetrics). LCMS: R_(T)=1.09 minutes, MS: 255(M+H).

¹H NMR (300 MHz, CDCl₃): 3.15 (m, 2H), 3.3 (m, 3H), 2.97 (m, 1H), 2.71(m, 1H), 2.47 (m, 1H), 1.98 (m, 2H), 1.96-1.67 (m, 4H), 1.46 (s, 9H),1.06 (d, 6.2 Hz, 3H).

Intermediate (xv) Preparation of 2(2S)-methyl-[1,3′(3′R)]bipyrrolidinyl

2-(2S)-Methyl-[1,3′(3′R)]bipyrrolidinyl-1′-carboxylic acid tert-butylester (7.91 g, 31.14 mmol) was treated with 28.8 mL of HCl in dioxane at0° C. The solution was stirred under nitrogen at r.t. overnight. BothTLC (10% MeOH in DCM) and LC/MS did not detect the starting material.The reaction was judged complete.

N₂ was passed through the solution with stirring. The outlet was passedthrough KOH solution to absorb HCl for 1 h. The solvent was removed byevaporation to dryness to get the title compound as a hygroscopic verythick gummy (2HCl salt, hydrated. Exact composition unknown), 8.07 g(˜100%). MS: 155 (M+H).

¹H NMR: (D2O, 300 MHz): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 (m, 1H) 3.5,(m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4 (m, 2H), 1.6 (m, 1H), 1.4(d, 6.0 Hz, 3H).

Intermediate (xvi) 2(2S)-Methyl-[1,3′(3′S)]bipyrrolidinyl

The title compound was prepared in a manner substantially the same asintermediate (xv) by acid hydrolysis of2-(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-carboxylic acid tert-butylester (Intermediate (x) obtained above).

LCMS: R_(T)=0.37 minutes, MS: 155 (M+H).

¹H NMR: (D2O, 300 MHz): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 (m, 1H) 3.5,(m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4 (m, 2H), 1.6 (m, 1H), 1.4(d, 6.0 Hz, 3H)

Intermediate (xvii) Preparation of2(2R)-methyl-[1,3′(3′S)]bipyrrolidinyl

The title compound was prepared in a manner substantially the same asintermediate (xv) by acid hydrolysis of2-(2R)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-carboxylic acid tert-butylester (Intermediate (xi) obtained above).

Intermediate (xviii) 2(2R)-Methyl-[1,3′(3′R)]bipyrrolidinyl

The title compound was prepared in a manner substantially the same asintermediate (xv) by acid hydrolysis of2-(2R)-methyl-[1,3′(3′R)]bipyrrolidinyl-1′-carboxylic acid tert-butylester (Intermediate (xiv) obtained above). MS: 155 (M+H).

¹H NMR: (D₂O, 300 MHz): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 (m, 1H) 3.5,(m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4 (m, 2H), 1.6 (m, 1H), 1.4(d, 6.0 Hz, 3H)

Intermediate (xix) 2-(2S)-Methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′(3′R)]bipyrrolidinyl

2(2S)-Methyl-[1,3′(3′R)]bipyrrolidinyl (0.23 g, 1.2 mmol) was dissolvedin anhydrous DMSO (5 mL) in a flask. To this solution was added5-fluoro-2-nitrotoluene (223 mg, 1.44 mmol), followed by powderedanhydrous potassium carbonate (662 mg, 4.8 mmol). The suspension washeated on an oil bath to 85° C. for 4 h when the starting material wasconsumed as shown by TLC (5% MeOH/DCM) and LC/MS. MS: 290 (base peak).

To the suspension were added 2 mL of water and 5 mL of DCM. The twolayers were separated, and the aqueous layer was extracted with DCM (10mL×2). The combined DCM extracts were washed with sodium bicarbonate (5mL), and brine (5 mL×2), dried (anhydrous potassium carbonate),filtered, and concentrated in vacuo. The crude product was purified on asilica gel column, eluted with 5% MeOH in DCM to get the title compoundas a yellow solid after drying. LCMS: R_(T)=1.38 minutes, MS: 290 (M+H).

¹H NMR (300 MHz, CDCl3): 8.10 (d, 9.1 Hz, 1H), 6.36 (dd, 9.2, 2.5 Hz,1H), 6.28 (d, 2.4 Hz, 1H), 3.654 (m, 2H), 3.37 (m, 3H), 2.99 (dt, 3.7Hz, 8.8 Hz, 1H), 2.84 (sixtet, 6.6 Hz, 1H), 2.65 (s, 3H), 2.56 (q, 8.1Hz, 1H), 2.31 (m, 2H), 2.11 (m, 2H) 1.87 (m, 1H), 1.08 (d, 6.2 Hz, 3H).

Analytical chiral HPLC conditions: Isocratic 100% isopropanol with 0.5%IPAmine 5 ml/min outlet pressure 150 bar, 200 nM;

Results: R_(T)=10.92 min; ee 100%

Intermediate (xx)2-(2S)-Methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′(3′S)]bipyrrolidinyl

The title compound was prepared in a manner substantially the same asintermediate (xix) by condensing 2(2S)-methyl-[1,3′(3S)]bipyrrolidinyland 5-fluoro-2-nitrotoluene. LCMS: R_(T)=1.43 minutes, MS: 290 (M+H).

¹H NMR (300 MHz, CDCl₃): 8.10 (d, 9.2 Hz, 1H), 6.36 (dd, 9.2, 2.8 Hz,1H), 6.28 (d, 2.2 Hz, 1H), 3.6 (m, 2H), 3.3 (m, 3H), 3.00-2.78 (dt, 3.5Hz, 8.8 Hz, 2H), 2.79 (m, 1H), 2.64 (s, 3H), 2.56 (m, 1H), 2.03 (m, 2H),1.98 (m, 2H) 1.45 (m, 1H), 1.08 (d, 6.2 Hz, 3H).

Analytical chiral HPLC conditions: Isocratic 100% isopropanol with 0.5%IPAmine 5 ml/min outlet pressure 150 bar, 200 nM;

Results: R_(T)=8.16 min; ee 100%

Intermediate (xxi)2-(2R)-Methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′(3′S)]bipyrrolidinyl

The title compound was prepared in a manner substantially the same asintermediate (xix) by condensing 2(2R)-methyl-[1,3′(3′S)]bipyrrolidinyland 5-fluoro-2-nitrotoluene. LCMS: R_(T)=1.41 minutes, MS: 290 (M+H).

¹H NMR (300 MHz, CDCl3): 8.10 (d, 9.1 Hz, 1H), 6.36 (dd, 9.2, 2.5 Hz,1H), 6.28 (d, 2.4 Hz, 1H), 3.654 (m, 2H), 3.37 (m, 3H), 2.99 (dt, 3.7Hz, 8.8 Hz, 1H), 2.84 (sixtet, 6.6 Hz, 1H), 2.65 (s, 3H), 2.56 (q, 8.1Hz, 1H), 2.31 (m, 2H), 2.11 (m, 2H) 1.87 (m, 1H), 1.08 (d, 6.2 Hz, 3H).

Analytical chiral HPLC conditions: Isocratic 100% isopropanol with 0.5%IPAmine 5 ml/min outlet pressure 150 bar, 200 nM;

Results: R_(T)=11.93 min; ee 100%

Intermediate (xxii)2-(2R)-Methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′(3′R)]bipyrrolidinyl

The title compound was prepared in a manner substantially the same asintermediate (xix) by condensing 2(2R)-Methyl-[1,3′(3′R)]bipyrrolidinyland 5-fluoro-2-nitrotoluene. LCMS: R_(T)=1.43 minutes, MS: 290 (M+H).

¹H NMR (300 MHz, CDCl₃): 8.10 (d, 9.2 Hz, 1H), 6.36 (dd, 9.2, 2.8 Hz,1H), 6.28 (d, 2.2 Hz, 1H), 3.6 (m, 2H), 3.3 (m, 3H), 3.00-2.78 (dt, 3.5Hz, 8.8 Hz, 2H), 2.79 (m, 1H), 2.64 (s, 3H), 2.56 (m, 1H), 2.03 (m, 2H),1.98 (m, 2H) 1.45 (m, 1H), 1.08 (d, 6.2 Hz, 3H).

Analytical chiral HPLC conditions: Isocratic 100% isopropanol with 0.5%IPAmine 5 ml/min outlet pressure 150 bar, 200 nM;

Results: R_(T)=8.95 min; ee 100%

Intermediate (xxiii) 2-Methyl-4-(2-(2S)-methyl-[1,3′(3′R)]bipyrrolidinyl-1′-yl)-phenylamine

A solution of2-(2S)-methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′(3′R)]bipyrrolidinyl(2.02 g, 6.98 mmol) in MeOH (40 mL) was de-aerated and nitrogen wasintroduced. To this solution was added Pd—C (10%, 0.2 g). This mixturewas stirred under H₂ atmosphere at r.t. for 4 h. TLC (10% MeOH in DCM)and LC/MS showed the reaction was complete, and the product was detectedby MS at 261. The mixture was passed through a Celite pad, rinsed withmethanol. The filtrate was concentrated to dryness, and further dried toyield the title compound as a reddish brown liquid after drying underhigh vacuum, 1.81 g (100%). LC/MS: 260, TLC (10% MeOH/DCM): 0.3 Rf.

This material is used immediately without storage and/or furtherpurification.

Intermediate (xxiv)2-Methyl-4-(2-(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenylamine

The title compound was prepared in a manner substantially the same asintermediate (xxiii) by hydrogenation of2-(2S)Methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′(3′S)]bipyrrolidinyl.LC/MS: 260, TLC (10% MeOH/DCM): 0.3 Rf.

Intermediate (xxv)2-Methyl-4-(2-(2R)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenylamine

The title compound was prepared in a manner substantially the same asintermediate (xxiii) by hydrogenation of2-(2R)-methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′(3′S)]bipyrrolidinyl.LC/MS: 260, TLC (10% MeOH/DCM): 0.3 Rf.

Intermediate (xxvi)2-Methyl-4-(2(2R)-methyl-[1,3′(3′R)]bipyrrolidinyl-1′-yl)-phenylamine

The title compound was prepared in a manner substantially the same asintermediate (xxiii) by hydrogenation of2-(2R)-Methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′(3′R)]bipyrrolidinyl.LC/MS: 260, TLC (10% MeOH/DCM): 0.3 Rf.

Example 14-Fluoro-N-[2-methyl-4-(2(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

2-Methyl-4-(2(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenylamine(200 mg, 0.77 mmol) was dissolved in DCM (10 mL). To this solution wastransferred a solution of 4-fluoro-benzoyl chloride (from Alfa Aesar,222 mg, 1.4 mmol) in DCM (2 mL), followed by pyridine (1 mL) at 0° C.The solution was stirred at 0° C. for 30 min. The ice-water bath wasremoved and the reaction was stirred at r.t. for 1.5 h when TLC (10%MeOH in DCM) and LC/MS showed that the reaction was complete and theproduct peak (396) was detected. The reaction was quenched with polymerbounded diethylenetriamine (4 mmol/g, 0.25 g), stirring at r.t. for 30min, then filtered and rinsed with DCM. The solvent was evaporated todryness, re-dissolved in DCM and washed with aqueous sodium bicarbonatesolution. The two layers were separated, and the aqueous layer wasextracted with DCM (5 mL×2). The combined DCM extracts were again washedwith sodium bicarbonate solution (5 mL), and brine (5 mL×2), dried(anhydrous potassium carbonate), filtered, and concentrated in vacuo.The crude product was purified on a silica gel column, elutedsuccessively with 2%, 7.5%, and 10% MeOH in DCM to obtain the titlecompound as a yellow tan solid in the form of a free base. This materialwas dissolved in DCM and ether (1:1 v/v, 5 mL), treated with 1N HCl (1mL) at 0° C. The solvent was evaporated and dried under high vacuum toobtain the title compound as a tan solid.

LCMS: R_(T)=2.26 minutes, MS: 382 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 8.06 (m, 1H), 7.89 (m, 1H), 7.47 (m,1H), 7.15 (m, 1H), 7.06 (m, 1H), 6.43-6.46 (m, 2H), 3.56 (m, 2H), 3.42(m, 2H), 3.30 (m, 2H), 3.07 (m, 1H), 2.78 (m, 1H), 2.27 (s, 3H), 2.21(m, 2H), 2.05-1.80 (m, 3H), 1.65 (m, 1H), 1.29 (d, 6.3 Hz, 3H).

Example 25-Fluoro-2-methyl-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoro-acetate

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(3-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with5-fluoro-2-methylbenzoyl chloride (from Alfa Aesar). MS: 396.3 (M+H).

Example 35-Fluoro-2-methyl-N-[2-methyl-4-(2(2S)-methyl-[1,3′(3′R)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

2-Methyl-4-(2(2S)-methyl-[1,3′(3′R)]bipyrrolidinyl-1′-yl)-phenylamine(200 mg, 0.77 mmol) was dissolved in DCM (10 mL). To this solution wasadded a solution of 5-fluoro-2-methylbenzoyl chloride (from Alfa Aesar,242 mg, 1.4 mmol) in DCM (2 mL), followed by pyridine (1 mL) at 0° C.The solution was stirred at 0° C. for 30 min. The ice-water bath wasremoved and the reaction was stirred at r.t. for 1.5 h when TLC (10%MeOH in DCM) and LC/MS showed that the reaction was complete and theproduct peak (396) was detected. The reaction was quenched with polymerbound diethylenetriamine (4 mmol/g, 0.25 g), stirring at r.t. for 30min, then filtered and rinsed with DCM. The solvent was evaporated todryness, re-dissolved in DCM and aqueous sodium bicarbonate solution.The two layers were separated, and the aqueous layer was extracted withDCM (5 mL×2). The combined DCM extracts were washed with sodiumbicarbonate (5 mL), and brine (5 mL×2), dried (anhydrous potassiumcarbonate), filtered, and concentrated in vacuo. The crude product waspurified on a silica gel column, eluted successively with 2%, 7.5%, and10% MeOH in DCM to obtain the title compound in the form of a free baseas a yellow tan solid. This material was dissolved in DCM and ether (1:1v/v, 5 mL), treated with 1N HCl (1 mL) at 0° C. The solvent wasevaporated and dried under high vacuum to obtain the title compound as atan solid.

LCMS: R_(T)=1.61 minutes, MS: 396 (M+H).

¹H NMR (DMSO-d6, 300 MHz), δ (ppm): 10.8 (bs, 1H), 9.59 (bs, 1H), 7.32(m, 2H), 7.14 (m, 1H), 7.17 (m, 2H), 6.51 (m, 2H), 4.15 (m, 1H), 3.56(m, 4H), 3.48 (m, 1H), 3.39 (m, 1H), 3.23 (m, 2H), 2.5-2.4 (m, 3H), 2.38(s, 3H), 2.22 (s, 3H), 1.95 (m, 2H), 1.66 (m, 1H), 1.45 (d, 6.4 Hz, 3H).

Example 4N-[4-(2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-trifluoromethyl-benzamidetrifluoro-acetate

The title compound was prepared in a manner substantially the same asExample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-trifluoromethyl-benzoyl chloride. MS: 418.2 (M+H).

Example 55-Fluoro-2-methyl-N-[2-methyl-4-(2(2R)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

2-Methyl-4-(2(2R)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenylamine(200 mg, 0.77 mmol) was dissolved in DCM (10 mL). To this solution wasadded a solution of 5-fluoro-2-methylbenzoyl chloride (from Alfa Aesar,242 mg, 1.4 mmol) in DCM (2 mL), followed by pyridine (1 mL) at 0° C.The solution was stirred at 0° C. for 30 min. The ice-water bath wasremoved and the reaction was stirred at r.t. for 1.5 h when TLC (10%MeOH in DCM) and LC/MS showed that the reaction was complete and theproduct peak (396) was detected. The reaction was quenched with polymerbound diethylenetriamine (4 mmol/g, 0.25 g), stirring at r.t. for 30min, then filtered and rinsed with DCM. The solvent was evaporated todryness, re-dissolved in DCM and NaHCO₃ aqueous solution. The two layerswere separated, and the aqueous layer was extracted with DCM (5 mL×2).The combined DCM extracts were washed with sodium bicarbonate (5 mL),and brine (5 mL×2), dried (anhydrous potassium carbonate), filtered, andconcentrated in vacuo. The crude product was purified on a silica gelcolumn by eluting successively with 2%, 7.5%, and 10% MeOH in DCM toobtain the title compound as a yellow tan solid in the form of a freebase. This material was dissolved in DCM and ether (1:1 v/v, 5 mL),treated with 1N HCl (1 mL) at 0° C. The solvent was evaporated and driedunder high vacuum to obtain the title compound as a tan solid. LCMS:R_(T)=1.59 minutes, MS: 396 (M+H).

¹H NMR (DMSO-d6, 300 MHz), δ (ppm): 10.8 (bs, 1H), 9.59 (bs, 1H), 7.32(m, 2H), 7.14 (m, 1H), 7.17 (m, 2H), 6.51 (m, 2H), 4.15 (m, 1H), 3.56(m, 4H), 3.48 (m, 1H), 3.39 (m, 1H), 3.23 (m, 2H), 2.5-2.4 (m, 3H), 2.38(s, 3H), 2.22 (s, 3H), 1.95 (m, 2H), 1.66 (m, 1H), 1.45 (d, 6.4 Hz, 3H).

Example 62-Fluoro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine (1.52 g,5.84 mmol) was dissolved in DCM (30 mL). To this solution wastransferred a solution of 2-fluorobenzoyl chloride in DCM (2 mL),followed by pyridine (7.5 mL). The solution was stirred at r.t. for 2 hwhen TLC (10% MeOH in DCM) and LC/MS showed that the reaction wascomplete. The reaction was quenched with polymer boundeddiethylenetriamine (4 mmol/g, 1.5 g) and the suspension was stirred for30 min. Then, 10 mL of DCM was added to the suspension and thesuspension was filtered through a Celite pad, rinsed with DCM and 10%MeOH in DCM. The crude product was purified on a silica gel columneluted with 2%, 5% and 7.5% MeOH in DCM to obtain the title compound asa yellow solid, 1.79 g (80%). LCMS: R_(T)=1.53 minutes, MS: 382 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): Two sets of signals were observed inabout 1:1.2 ratio and the spectra were closely overlapping. The observedchemical shifts are as follows: 8.26 (m), 7.78 (m), 7.65 (m), 7.5 (m),7.3 (m), 7.15 (m), 6.4 (m), 3.5-3.2 (m), 3.00 (m), 2.80 (m), 2.55 (m),2.3 (m), 2.10-1.6 (m), 2.45 (m), 1.08 (d).

Example 74-Fluoro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-fluorobenzoyl chloride. LCMS: R_(T)=1.54 minutes, MS: 382 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): Two sets of signals were observed andthe spectra were closely overlapping. The observed chemical shifts areas follows: 1.86 (m), 7.48, 7.13 (m), 7.11 (m), 6.41 (m), 3.53-3.34 (m),2.29 (m), 2.89 (m), 2.62 (m), 2.60-1.77 (m), 1.57 (m), 1.21 (d, 6.1 Hz),1.20 (d, 5.8 Hz).

Example 82-Fluoro-N-[2-methyl-4-(2-(2R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-(R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-fluorobenzoyl chloride. LCMS: R_(T)=1.70 minutes, MS: 382 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): Two sets of signals were observed inabout 1:1.2 ratio and the spectra were closely overlapping. The observedchemical shifts are as follows: 12.5 (bs), 8.26 (m), 8.00 (m), 7.78 (m),7.60 (m), 7.3 (m), 6.55 (m), 4.2 (bs), 3.98 (bs), 3.68-3.34 (m), 2.29(m), 2.89 (m), 2.62 (m), 1.90 (m), 1.6 (m).

Example 94-Fluoro-N-[2-methyl-4-(2-(2R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-(R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-fluorobenzoyl chloride. LCMS: R_(T)=1.57 minutes, MS: 382 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): Two sets of signals were observed inabout 1:3 ratio and the spectra were closely overlapping. The observedchemical shifts are as follows: 12.8 (bs), 7.86 (m), 7.48, 7.13-6.95(m), 6.45 (m), 4.2, 3.9, 3.85-3.10 (m), 2.6-2.0 (m), 2.62 (m), 2.0-1.57(m).

Example 105-Fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with5-fluoro-2-methyl-benzoyl chloride (from Alfa Aesar). LCMS: R_(T)=1.56minutes, MS: 396 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.48 (d, 7.4 Hz, 1H), 7.23 (m, 2H),7.04 (m, 1H), 6.42 (m, 2H), 3.53-3.05 (m, 6H), 2.81 (m, 1H), 2.54 (m,1H), 2.49 (bs, 3H), 2.28 (bs, 3H), 2.2-1.95 (m, 3H), 1.70 (m, 4H), 1.15(d, 6.0 Hz, 3H).

Example 115-Fluoro-2-methyl-N-[2-methyl-4-(2-(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with5-fluoro-2-methyl-benzoyl chloride (from Alfa Aesar).

LCMS: R_(T)=2.14 minutes, MS: 396 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.48 (d, 7.4 Hz, 1H), 7.23 (m, 1H),7.04 (m, 2H), 6.42 (m, 2H), 3.53 (m, 1H), 3.40-3.27 (m, 4H), 3.05 (m,1H), 2.81 (m, 1H), 2.54 (m, 1H), 2.49 (bs, 3H), 2.28 (bs, 3H), 2.2-1.95(m, 3H), 1.70 (m, 4H), 1.15 (d, 6.0 Hz, 3H).

Example 125-Fluoro-2-methyl-N-[2-methyl-4-(2-(R)-methyl-[1,3′(R)]bipyrrolidinyl-1′-yl)-phenyl]-benzamidehydrochloride

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-(R)-methyl-[1,3′(R)]bipyrrolidinyl-1′-yl)-phenylamine with5-fluoro-2-methyl-benzoyl chloride (from Alfa Aesar).

LCMS: R_(T)=1.61 minutes, MS: 396 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.48 (d, 7.4 Hz, 1H), 7.23 (m, 1H),7.04 (m, 2H), 6.42 (m, 2H), 3.53 (m, 1H), 3.40-3.27 (m, 4H), 3.05 (m,1H), 2.81 (m, 1H), 2.54 (m, 1H), 2.49 (bs, 3H), 2.28 (bs, 3H), 2.2-1.95(m, 3H), 1.70 (m, 4H), 1.15 (d, 6.0 Hz, 3H).

Example 133-Fluoro-N-[2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with3-fluoro-benzoic acid. LCMS: R_(T)=2.26 minutes, MS: 382 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.65 (m, 2H), 7.47 (m, 2H), 7.23 (m,1H), 6.45-6.42 (m, 2H), 3.54 (t, 7.5 Hz, 1H), 3.39 (m, 3H), 3.31 (m,1H), 3.10 (m, 1H), 2.88 (m, 1H), 2.60 (q, 8.4 Hz, 1H), 2.28 (s, 3H),2.23-1.71 (m, 5H), 1.53 (m, 1H), 1.19 (d, 6.3 Hz, 3H).

Example 144-Chloro-N-[2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with4-chloro-benzoyl chloride. LCMS: R_(T)=3.96 minutes, MS: 398 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 8.19 (m, 1H), 7.94 (m, 1H), 7.46 (d,7.2 Hz, 1H), 7.23 (m, 1H), 6.43-6.46 (m, 2H), 3.56 (m, 2H), 3.53 (m,1H), 3.40-3.24 (m, 3H), 3.1 (m, 1H), 2.78-2.50 (m, 3H), 2.27 (s, 3H),2.21 (m, 2H), 2.05-1.80 (m, 3H), 1.75 (m, 1H), 1.50 (m, 1H), 1.17 (d,6.3 Hz, 3H).

Example 155-Fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with5-fluoro-2-trifluoromethyl-benzoyl chloride. LCMS: R_(T)=2.53 minutes,MS: 450 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.78 (dd, 5.1 Hz, 8.4 Hz, 1H), 7.49(d, 8.4 Hz, 1H), 7.74 (dd, 2.7 Hz, 8.4 Hz, 1H), 7.06 (s, 1H), 6.46-6.42(m, 2H), 3.55 (m, 1H), 3.43 (m, 2H), 3.31 (m, 2H), 2.92 (m, 1H), 2.64(m, 1H), 2.28 (s, 3H), 2.24-1.51 (m, 7H), 1.22 (d, 6.6 Hz, 3H).

Example 16 2,3-Dihydro-benzofuran-5-carboxylic acid[2-methyl-4-(2(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenyl]-amide,trifluoro-acetic acid

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2(2S)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-yl)-phenylaminewith 2,3-dihydro-benzofuran-5-carbony chloride. LCMS: R_(T)=1.19minutes, MS: 406.2 (M+H).

Example 174-Methanesulfonyl-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-methanesulfonyl-benzoyl chloride. MS: 442.2 (M+H).

Example 182-Fluoro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 2-fluoro-benzoyl chloride. MS: 436.2 (M+H).

Example 194-Difluoromethoxy-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-difluoro-methoxy-benzoyl chloride. MS: 430.2 (M+H).

Example 203-Fluoro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-fluoro-benzoyl chloride. MS: 368.2 (M+H).

Example 21(E)-N-[4-(2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-pyridin-3-yl-acrylamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-pyridin-3-yl-acryloyl chloride. MS: 377.3 (M+H).

Example 222,5-Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2,5-Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylicacid. MS: 462.3 (M+H).

Example 234-Cyano-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-cyano-benzoyl chloride. MS: 389.2 (M+H).

Example 243-Fluoro-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-fluoro-benzoyl chloride. MS: 382.2 (M+H).

Example 25 Tetrahydro-furan-2-carboxylic acid[2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine withtetrahydro-furan-2-carboxylic acid. MS: 358.2 (M+H).

Example 26 6-Chloro-imidazo[1,2-a]pyridine-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-Chloro-imidazo[1,2-a]pyridine-2-carboxylic acid. MS: 438.4 (M+H).

Example 27N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-trifluoromethyl-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-trifluoro-methyl-benzoyl chloride. MS: 432.2 (M+H).

Example 28 Thiophene-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withthiophene-2-carboxylic acid. MS: 370.2 (M+H).

Example 29 4-Oxo-4,5,6,7-tetrahydro-benzofuran-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-oxo-4,5,6,7-tetrahydro-benzofuran-2-carboxylic acid. MS: 422.4 (M+H).

Example 304-Isopropyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-sulfamoyl-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-isopropyl-3-sulfamoyl-benzoic acid. MS: 485.3 (M+H).

Example 31N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-(1H-pyrazol-3-yl)-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-(1H-pyrazol-3-yl)-benzoic acid. MS: 430.3 (M+H).

Example 32 Benzofuran-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withbenzofuran-5-carboxylic acid. MS: 404.4 (M+H).

Example 33 6-Methoxy-benzofuran-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-methoxy-benzofuran-2-carboxylic acid. MS: 434.2 (M+H).

Example 34 2-Pyridin-3-yl-1H-benzoimidazole-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-pyridin-3-yl-1H-benzoimidazole-5-carboxylic acid. MS: 481.3 (M+H).

Example 35 6-Chloro-4-oxo-4H-chromene-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-chloro-4-oxo-4H-chromene-2-carboxylic acid. MS: 466.2 (M+H).

Example 36 N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamidetrifluoro-acetate

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withpyridine-3-carboxylic acid. MS: 365.22 (M+H).

Example 37 1H-Indole-2-carboxylic acid[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide trifluoro-acetate

The title compound was prepared in a manner substantially the same asExample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1H-Indole-2-carboxylic acid. MS: 389.22 (M+H).

Example 385-Chloro-6-(2-hydroxy-ethylamino)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with5-chloro-6-(2-hydroxy-ethylamino)-nicotinic acid. MS: 458.4 (M+H).

Example 396-Benzyloxymethyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-benzyloxy-methyl-nicotininic acid. MS: 485.5 (M+H).

Example 40 2-Pyridin-4-yl-thiazole-4-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-pyridin-4-yl-thiazole-4-carboxylic acid. MS: 448.2 (M+H).

Example 41 Thiophene-2-carboxylic acid[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound is prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withthiophene-2-carboxylic acid. MS: 370.2 (M+H).

Example 424-(4,6-Dimethyl-pyrimidin-2-ylamino)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-(4,6-dimethyl-pyrimidin-2-ylamino)benzoic acid. MS: 485.3 (M+H).

Example 43 1-Acetyl-pyrrolidine-2-carboxylic acid[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide trifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1-acetyl-pyrrolidine-2-carboxylic acid. MS: 385.3 (M+H).

Example 445-Fluoro-2-methyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with5-fluoro-2-methyl benzoic acid. MS: 382.3 (M+H).

Example 45 1H-Indole-2-carboxylic acid[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1H-Indole-2-carboxylic acid. MS: 403.3 (M+H).

Example 463-Dimethylamino-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-dimethyl-amino benzoic acid. MS: 407.3 (M+H).

Example 47N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2-phenoxy-acetamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-phenoxy-acetic acid. MS: 394.2 (M+H).

Example 484-Methanesulfonyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-methane-sulfonyl benzoic acid. MS: 442.2 (M+H).

Example 49 5-Methoxy-benzofuran-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with5-methoxy-benzofuran-2-carboxylic acid. MS: 434.2 (M+H).

Example 50 4-Hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid. MS: 446.5(M+H).

Example 51 2-Pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid. MS: 481.3 (M+H).

Example 52 1H-Indole-5-carboxylic acid[2-methyl-4-(2(S)-methyl-[1,3′(5)]-bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with1H-indole-5-carboxylic acid. MS: 403.4 (M+H).

Example 53 Benzo[1,3]dioxole-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withbenzo[1,3]-dioxole-5-carboxylic acid. MS: 408.4 (M+H).

Example 544-(Formyl-methyl-amino)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-(formyl-methyl-amino)-benzoic acid. MS: 421.3 (M+H).

Example 554-(1-Acetyl-piperidin-3-yl)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-(1-acetyl-piperidin-3-yl)-benzoic acid. MS: 489.3 (M+H).

Example 562-Fluoro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-fluoro-benzoic acid. MS: 368.2 (M+H).

Example 57N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoic acid. MS: 457.3 (M+H).

Example 58N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-morpholin-4-ylmethyl-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-morpholin-4-ylmethyl-benzoic acid. MS: 463.4 (M+H).

Example 59(E)-3-(3-Fluoro-phenyl)-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acrylamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with(E)-3-(3-fluoro-phenyl)-acrylic acid. MS: 394.2 (M+H).

Example 60(E)-N-[4-(2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-3-pyridin-3-yl-acrylamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith (E)-3-pyridin-3-yl-acrylic acid. MS: 445.2 (M+H).

Example 61 1-Acetyl-pyrrolidine-2-carboxylic acid[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1-acetyl-pyrrolidine-2-carboxylic acid. MS: 399.2 (M+H).

Example 62 Pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-{[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide}

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withpyridine-2,5-dicarboxylic acid 2-[(2-methoxy-ethyl)-amide]. MS: 466.3(M+H).

Example 632,4-Dimethyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 2,4-dimethyl benzoyl chloride. MS: 446.2 (M+H).

Example 644-(3,5-Dimethyl-1H-pyrazol-4-yl)-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-(3,5-dimethyl-1H-pyrazol-4-yl)benzoic acid. MS: 458.3 (M+H).

Example 65N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-(2-oxo-pyrrolidin-1-yl)-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-(2-oxo-pyrrolidin-1-yl)-benzoic acid. MS: 447.5 (M+H).

Example 66 1H-Indole-6-carboxylic acid[2-methyl-4-(2(S)-methyl-[1,3′(S)]-bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling 2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with 1H-indole-6-carboxylic acid.MS: 403.4 (M+H).

Example 67 Imidazo[1,2-a]pyridine-8-carboxylic acid[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide trifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withimidazo-[1,2-a]pyridine-8-carboxylic acid. MS: 390.3 (M+H).

Example 684-Cyano-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-cyano-benzoic acid. MS: 389.2 (M+H).

Example 69 Imidazo[1,2-a]pyridine-8-carboxylic acid[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withimidazo-[1,2-a]pyridine-8-carboxylic acid. MS: 404.3 (M+H).

Example 70 1H-Indole-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1H-indole-2-carboxylic acid. MS: 403.2 (M+H).

Example 712-Methanesulfonyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-trifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-methane-sulfonyl-acetic acid. MS: 380.2 (M+H).

Example 72 6-Fluoro-2-methyl-quinoline-3-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-fluoro-2-methyl-quinoline-3-carboxylic acid. MS: 447.4 (M+H).

Example 73 Benzofuran-6-carboxylic acid[2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine withbenzofuran-6-carboxylic acid. MS: 404.2 (M+H).

Example 74(E)-3-(3-Fluoro-phenyl)-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acrylamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenylamine with(E)-3-(3-fluoro-phenyl)-acrylic acid. MS: 408.2 (M+H).

Example 752-Methanesulfonyl-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-methane-sulfonyl-acetic acid. MS: 380.2 (M+H).

Example 76 1-Acetyl-pyrrolidine-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1-acetyl-pyrrolidine-2-carboxylic acid. MS: 399.3 (M+H).

Example 774-Chloro-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-chloro-benzoyl chloride. MS: 398.2 (M+H).

Example 78 1H-Indole-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1H-indole-5-carboxylic acid. MS: 403.3 (M+H).

Example 79N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-oxazol-5-yl-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-oxazol-5-yl-benzoyl chloride. MS: 431.3 (M+H).

Example 803-Methoxy-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 3-methoxy-benzoyl chloride. MS: 448.2 (M+H).

Example 814-Chloro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-chloro-benzoyl chloride. MS: 398.2 (M+H).

Example 824-Dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-dimethylamino-benzoic acid. MS: 393.2 (M+H).

Example 83 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid. MS: 422.4 (M+H).

Example 845-Fluoro-2-methyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 5-fluoro-2-methyl benzoyl chloride. MS: 450.2 (M+H).

Example 853-Dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 3-dimethylaminobenzoic acid. MS: 393.3 (M+H).

Example 86 6-Methyl-pyridine-2-carboxylic acid[2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with6-methyl-pyridine-2-carboxylic acid. MS: 379.2 (M+H).

Example 874-Methoxy-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-methoxy-benzoyl chloride. MS: 394.2 (M+H).

Example 88 2-Pyridin-3-yl-thiazole-4-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-pyridin-3-yl-thiazole-4-carboxylic acid. MS: 448.2 (M+H).

Example 893,5-Dichloro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 3,5-dichloro-benzoyl chloride. MS: 486.1 (M+H).

Example 90 2-Methyl-1H-benzoimidazole-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-methyl-1H-benzoimidazole-5-carboxylic acid. MS: 418.3 (M+H).

Example 913,5-Dichloro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3,5-dichloro-benzoyl chloride. MS: 418.1 (M+H).

Example 92N-[3-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-trifluoromethyl-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-trifluoro-methyl-benzoyl chloride. MS: 432.2 (M+H).

Example 932-Fluoro-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-fluoro-benzoyl chloride. MS: 382.2 (M+H).

Example 94 3-Phenyl-propynoic acid[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-phenyl-propynoic acid. MS: 388.2 (M+H).

Example 95 6-Methyl-4-oxo-4H-chromene-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-methyl-4-oxo-4H-chromene-2-carboxylic acid. MS: 446.4 (M+H).

Example 96 [1,6]Naphthyridine-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with[1,6]naphthyridine-2-carboxylic acid. MS: 416.4 (M+H).

Example 973-Methanesulfonyl-4-methyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-methane-sulfonyl-4-methyl-benzoyl chloride. MS: 456.2 (M+H).

Example 984-{4-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylcarbamoyl]-phenoxy}-benzoicacid

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4,4′-biscarboxydiphenyl ether. MS: 500.3 (M+H).

Example 992-Dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 2-dimethylamino-benzoic acid. MS: 461.3 (M+H).

Example 100N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-6-morpholin-4-yl-nicotinamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-morpholin-4-yl-nicotinic acid. MS: 450.5 (M+H).

Example 101 5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid. MS: 445.4 (M+H).

Example 102 2,3-Dihydro-benzofuran-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2,3-dihydro-benzofuran-5-carboxylic acid. MS: 406.4 (M+H).

Example 103 Thiophene-2-carboxylic acid[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide trifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withthiophene-2-carboxylic acid. MS: 356.2 (M+H).

Example 1044-Methanesulfonyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-methanesulfonyl-benzoyl chloride. MS: 428.2 (M+H).

Example 105 4-Benzoyl-1H-pyrrole-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-benzoyl-1H-pyrrole-2-carboxylic acid. MS: 457.4 (M+H).

Example 106 1-Isopropyl-1H-benzotriazole-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1-isopropyl-1H-benzotriazole-5-carboxylic acid. MS: 447.3 (M+H).

Example 1072-Methanesulfonyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-acetamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 2-methanesulfonyl acetic acid. MS: 434.1 (M+H).

Example 1082-Dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-dimethylaminobenzoic acid. MS: 393.3 (M+H).

Example 1093-Fluoro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 3-fluoro-benzoyl chloride. MS: 436.2 (M+H).

Example 1104-Chloro-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-chloro-benzoyl chloride. MS: 384.2 (M+H).

Example 111 Quinoline-3-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withquinoline-3-carboxylic acid. MS: 415.3 (M+H).

Example 1124-Imidazol-1-yl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-imidazol-1-yl benzoic acid. MS: 430.5 (M+H).

Example 113 1H-Indole-6-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with1H-indole-6-carboxylic acid. MS: 403.3 (M+H).

Example 114 6-Methoxy-1H-indazole-3-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-methoxy-1H-indazole-3-carboxylic acid. MS: 434.3 (M+H).

Example 1152-Methanesulfonyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-acetamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-methanesulfonyl acetic acid. MS: 366.2 (M+H).

Example 1162-Dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-acetamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 2-dimethylamino acetic acid. MS: 399.3 (M+H).

Example 1174-Cyano-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 4-cyano-benzoyl chloride. MS: 443.2 (M+H).

Example 118N-[4-(2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with nicotinic acid.MS: 351.2 (M+H).

Example 119 Imidazo[1,2-a]pyridine-8-carboxylic acid[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-amidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith imidazo[1,2-a]pyridine-8-carboxylic acid. MS: 458.2 (M+H).

Example 120N-[4-(2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2-phenoxy-acetamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with phenoxy-aceticacid. MS: 380.2 (M+H).

Example 121 4-Methoxy-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-methoxy-benzoyl chloride. MS: 380.2 (M+H).

Example 122 2-Oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid. MS: 420.3 (M+H).

Example 123N-[3-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-morpholin-4-ylmethyl-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-morpholin-4-ylmethyl-benzoyl chloride. MS: 463.3 (M+H).

Example 124N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-(1-propoxy-ethyl)-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-(1-propoxy-ethyl)-benzoic acid. MS: 463.3 (M+H).

Example 125N-[4-(2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-nicotinamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith nicotinic acid. MS: 419.2 (M+H).

Example 1264-[(4,6-Dimethyl-pyrimidin-2-yl)-methyl-amino]-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-[4(4,6-dimethyl-pyrimidin-2-yl)-methyl-amino]-benzoic acid. MS: 499.5(M+H).

Example 1273,5-Dichloro-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3,5-dichloro-benzoic acid. MS: 432.2 (M+H).

Example 1283-Dimethylamino-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 3-dimethylamino-benzoic acid. MS: 461.3 (M+H).

Example 1293-Methoxy-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-methoxy-benzoic acid. MS: 394.2 (M+H).

Example 1304-Dimethylamino-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-dimethylamino-benzoic acid. MS: 407.3 (M+H).

Example 1312,4-Dimethyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2,4-dimethyl-benzoyl chloride. MS: 378.2 (M+H).

Example 1324-Methanesulfonyl-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 4-methanesulfonyl-benzoic acid. MS: 496.2 (M+H).

Example 133N-[4-(2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2-phenoxy-acetamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith phenoxy-acetic acid. MS: 448.2 (M+H).

Example 1342,4-Dimethyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2,4-dimethyl-benzoyl chloride. MS: 392.2 (M+H).

Example 135

Benzo[d]imidazo[2,1-b]thiazole-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withbenzo[d]imidazo[2,1-b]thiazole-2-carboxylic acid. MS: 460.4 (M+H).

Example 1364-Methoxy-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylaminewith 4-methoxy benzoic acid. MS: 448.2 (M+H).

Example 137N-[3-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2-phenoxy-acetamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withphenoxy-acetic acid. MS: 394.3 (M+H).

Example 1383-Methoxy-N-[4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-methoxy-benzoic acid. MS: 380.2 (M+H).

Example 139(E)-N-[3-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-pyridin-3-yl-acrylamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-pyridin-3-yl-acrylic acid. MS: 391.3 (M+H).

Example 140(E)-N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-3-pyridin-3-yl-acrylamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-pyridin-3-yl-acrylic acid. MS: 391.3 (M+H).

Example 1412,4-Dimethyl-N-[3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with2,4-dimethyl-benzoyl chloride. MS: 392.3 (M+H).

Example 142N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-4-[1,2,4]triazol-1-yl-benzamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with4-[1,2,4]triazol-1-yl-benzoic acid. MS: 431.3 (M+H).

Example 1433-Fluoro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3-fluoro-benzoyl chloride. MS: 382.2 (M+H).

Example 1443,5-Dichloro-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with3,5-dichloro-benzoyl chloride. MS: 432.2 (M+H).

Example 145N-[3-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-nicotinamidetrifluoroacetate

The title compound was prepared in a manner substantially the same asexample 1 by coupling3-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine withnicotinic acid. MS: 365.2 (M+H).

Example 146 5-Methoxy-1H-indole-2-carboxylic acid[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with5-methoxy-1H-indole-2-carboxylic acid. MS: 433.2 (M+H).

Example 147N-[2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-6-pyrazol-1-yl-nicotinamide

The title compound was prepared in a manner substantially the same asexample 1 by coupling2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with6-pyrazol-1-yl-nicotinic acid. MS: 431.4 (M+H).

BIOLOGICAL EXAMPLES Example 148

This Example demonstrates the efficacy of compounds of this invention asH3 receptor ligands. The compounds of this invention have beendemonstrated to displace [³H]-Methylhistamine radioligand binding tomammalian cell membranes expressing rhesus (Macacca Mulatta) H3receptor. These compounds display rhesus H3 affinity constants (Ki) inthe range of 1 μM to <1 nM. Additionally, the compounds of thisinvention have been demonstrated by GTPγS radioligand binding assay toinhibit rhesus H3 constitutive functional activity in cell membranes.This inhibition of basal rhesus H3-mediated GTPγS radioligand bindingdemonstrates that the compounds of this invention find utility asinverse agonists. These compounds decreased rhesus H3 GTPγS radioligandbinding by 0-40% below basal levels.

Rhesus H3 membranes were prepared from the Flp-In T-REx 293 Cell Line(Invitrogen) stably transfected with pcDNA5/FRT/TO (Invitrogen)containing the rhesus monkey (Macacca Mulatta) 445 amino acid H3receptor. (Genbank #AY231164). Stably transfected cultures wereamplified in tissue culture flasks by standard tissue culture methodsand induced to express rhesus H3 by exposure to 500 ng/ml tetracycline(Cellgro) for 24 hours. After induction, cells were dissociated fromflasks utilizing Cell Stripper (Cellgro). Cells were centrifuged (1K×g,5 min) and pellet frozen in an ethanol-dry ice bath to disrupt cellmembranes. Frozen cell pellet was re-suspended in 5 mM HEPES (pH 7.4,Invitrogen) at 10 ml/1000 cm2 of harvested cells. The cell suspensionwas drawn through an 18 gauge needle (2-3×) followed by a 23 gaugeneedle (2-3×) to further disrupt cell membranes. The cell suspension wascentrifuged (40K×g, 30 min). Cell membrane pellet was re-suspended in 5mM HEPES (pH 7.4, Invitrogen) at a final protein concentration of 10mg/ml. Rhesus H3 membranes were stored under liquid nitrogen prior touse in [3H]-Methylhistamine and GTPγS radioligand binding assays.

Rhesus H3 radioligand binding assay was performed using rhesus H3receptor membranes (prepared as described above), [3H]-Methylhistamine(Perkin Elmer) and WGA SPA beads (wheat germ agglutinin scintillationproximity assay) beads (Amersham). The assay was performed in 96-wellOpti-Plates (Packard). Each reaction contained 50 μl rhesus H3 membranes(20-30 μg total protein), 50 μl WGA SPA beads (0.1 μg) and 50 μl of 83Ci/mmol [³H]-Methylhistamine (final concentration 2 nM) and 50 μl oftested compound. The compounds of this invention and/or vehicle werediluted with binding buffer from 10 mM DMSO stocks. Assay plates weresealed with TopSeal (Perkin Elmer) and mixed on shaker (25° C., 1 hour).Assay plates were read on TopCount scintillation counter (Packard).Results were analyzed by Hill transformation and Ki values weredetermined by Cheng-Prusoff equation. The observed binding data for afew of the representative compounds of this invention are summarized inTable 1.

TABLE 1 Affinity: ki in Inverse Agonism: % Rhesus H3 inhibition of BasalGTPγS Example No. membrane (nM) binding in Rhesus H3 7 2.06 −31 52 0.77−17 73 0.78 −15 86 1.42 −18

Example 149

This Example illustrates that the stereochemistry of the compounds ofthis invention has an effect on the biological activity. A few of therepresentative compounds of this invention were used in this example toshow this difference in biological activity based on the stereoisomericform. All of the compounds of this Example were tested for H3 receptorligand activity in accordance with the procedures as set forth inExample 148. The results are tabulated in Table 2.

TABLE 2 Affinity: ki in Rhesus H3 Example No. membrane (nM) 3 7.3 5120.8 11 2.5 12 147.2

Example 150

This Example illustrates selective affinity of the compounds of thisinvention at H3 receptors and exhibit low activity at the MCH-1 receptorsite.

The H3 affinity of the compounds of this invention was measured inaccordance with the procedures set forth in Example 148.

The activity of the compounds of this invention at the MCH-1 receptorsite, if any, was measured by the procedures as set forth below.

-   Test Compounds: The compounds of this invention were stored in a    96-well microtiter plates (1 nL, 10 mM, 100% DMSO). Each of the test    sample was diluted with 249 μL of 100% DMSO (dilution 1:250). The    test compounds were further diluted 1:4 (0.1% DMSO) during assay    resulting in the final concentration of test compounds of this    invention to be 10 nM.-   Negative Control: 40 μM of MCH-1 in assay buffer with 0.4% DMSO were    transferred to the dilution microtiter plates for control which    resulted in final concentration of 10 nM.-   Blank: Assay buffer containing 0.4% DMSO were transferred to the    dilution microtiter plates for blanks-   Assay Procedure: The filter plates with 250 mL of 0.5%    PEI-solution/well were incubated for 2 hours at room temperature.    PEI was removed by vacuum filtration just before pipetting (Univac    Polyfiltronic/Whatman). The solution of the compound as prepared    above (50 μL), or MCH-1 (negative control) or Puffer/DMSO (positive    control) were added to 96-well round bottom microtiter plate. Then    50 μl of [¹²⁵J]-ligand solution was added followed by 100 μl of    membrane suspension. The plates were closed with the lids, and    incubated for 60 min. at 25° C. The samples were transferred to GF/B    filter plate. The reaction mixture was removed by vacuum filtration,    washed 4× with 300 μl ice-cold washing buffer and the washing    solution was removed by vacuum filtration. The rubber layer at the    bottom of the plate was then removed and the filters were dried over    night at room temperature. 25 μl of scintillation cocktail was added    and the plates were sealed and, plate frames were added and    incubated for 1 hour at room temperature. The radioactivity was then    measured, settings ¹²⁵J standard, 30 sec./well. From this the    percent inhibition of ligand binding was measured.-   Results: In general the compounds of this invention exhibited a    rhesus H3 binding ki value in the range of from about 400 nM to less    than 1 nM, whereas the percent inhibition of ligand binding at MCH-1    receptor was less than 40% at 10 μM concentration. This comparative    Example demonstrates that the compounds of this invention can be    more than thousand times more selective at H3 receptor site than at    MCH-1 receptor site.

Example 151

This Example illustrates the study of efficacy of the compounds of thisinvention in enhancing the wakefulness in animal models.

Male Sprague Dawley rats (Charles River, France) weighing 250±10 g wereanaesthetized with Zoletil® 50 (60 mg/kg ip) and mounted in astereotaxic apparatus. Cortical electrodes (small stainless steel screwelectrodes of 0.9 mm in diameter) were screwed into the bone over thesensorimotor cortex (1.5 mm lateral to the median suture and 1.5 mmbehind the fronto-parietal suture), the visual cortex (1.5 mm lateral tothe median suture and 1.5 mm in front of the parieto-occipital suture)and over the cerebellum (reference electrode). Cortical electrodes wereattached to a connector (Winchester, 7-lead) and fixed with dentalcement to the cranium.

After three weeks of post-operative recovery, animals were placed inplexiglass cylinders (60 cm diameter) with free access to food andwater. The temperature of the room was kept constant (21±1° C.) andlights were on from 7 a.m. to 7 p.m. The rats were recorded from 10 a.m.to 4 p.m. during three consecutive days: control day (D1), drug day (D2)and post drug day (D3). Vehicle (D1 and D3) or drug (D2) wereadministered 15 min before the recording.

Activity in sensorimotor and visual cortices were recorded by comparisonwith the reference electrode placed over the cerebellar cortex. Threestages were differentiated:

-   -   wakefulness (W) characterized by low voltage fast        electrocortical (ECoG) activity;    -   NREM sleep (non rapid eye movement or slow wave sleep: SWS)        characterized by an increase in electrocortical activity;        development of high-amplitude slow waves with some bursts of        sleep spindles;    -   REM sleep (rapid eye movement or paradoxical sleep: PS)        characterized by hypersynchronization of the theta rhythm in the        visual area.

Analysis of the ECoG signal was performed automatically by means of acomputerized system discriminating between the various sleep phasesusing sequential spectral analysis of ten seconds periods (Deltamed'ssoftware “Coherence”).

The compounds of this invention were dissolved in 0.6% MTC tween andadministered by oral route (po). The volume of injection was 0.5 ml/100g of body weight.

Two types of analysis were used to quantify the effects of the compoundsof this invention on sleep-wakefulness variables: the one hour-periodand the six hour-period analysis.

The results are expressed in minutes (one hour-period analysis) or asthe percentage of the control values (100%). Statistical analysis of thedata was carried out using the Student's t test for paired values todetermine significant variations from control values.

Example 152 Stress-Induced Ultrasonic Vocalizations Test in Adult Rats

This Example illustrates the study of efficacy of the compounds of thisinvention as antidepressive agents in animal models.

The procedure used was adapted from the technique described by Van DerPoel A. M, Noach E. J. K, Miczek K. A (1989) Temporal patterning ofultrasonic distress calls in the adult rat: effects of morphine andbenzodiazepines. Psychopharmacology 97:147-8. Rats were placed for atraining session in a cage with a stainless steel grid floor (MEDAssociates, Inc., St. Albans, Vt.). Four electric shocks (0.8 mA, 3 s)were delivered every 7 s and ultrasonic vocalizations (UV, 22 KHz) weresubsequently recorded with the Ultravox system (Noldus, Wageningen, TheNetherlands) during 2 min. A modified ultrasound detector (Mini-3 batmodel) connected to a microphone was used to transform ultrasonic soundinto audible sound. The signal was then filtered and sent to a computerwhere the Ultravox software recorded each bout of UV that lasted morethan 10 ms. Rats were selected on the basis of their UV duration (>40 s)and subjected to the test, 4 h after training. For the test, rats wereplaced in the same cage as that used for training. One electric shock(0.8 mA, 3 s) was delivered and UV (duration and frequency) weresubsequently recorded with the Ultravox system during 2 min. Thecompounds of this invention were administered p.o. 60 min beforetesting.

Example 153 Forced-Swimming Test in Rats

This Example further illustrates the study of efficacy of the compoundsof this invention as antidepressive agents in animal models.

The procedure was a modification of that described by Porsolt et al.(1977) Depression: a new animal model sensitive to antidepressanttreatments. Nature 266:730-2. Rats were placed in individual glasscylinder (40 cm height, 17 cm diameter) containing water (21° C.) to aheight of 30 cm. Two swimming sessions were conducted (a 15-min trainingsession followed 24 h later by a 6-min test). After each swimmingsession, rats were placed under a heating lamp to avoid hypothermia. Theduration of immobility was measured during the 6-min test. The compoundsof this invention were administered p.o. twice (15 min after trainingsession and 60 min before the test).

Although the invention has been illustrated by certain of the precedingexamples, it is not to be construed as being limited thereby; butrather, the invention encompasses the generic area as hereinbeforedisclosed. Various modifications and embodiments can be made withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A compound of formula (I):

wherein R, R₁, R₂ and R₃ are the same or different and independently ofeach other chosen from hydrogen, (C₁-C₄)alkyl or CF₃; R₄ is selectedfrom the group consisting of dimethylaminomethyl, methanesulfonylmethyl,phenoxymethyl, vinylbenzene, ethynylbenzene, vinylpyridine, phenyl,benzofuranyl, dihydro-benzofuranyl, oxo-tetrahydro-benzofuranyl,benzodioxolyl, oxo-chromenyl, dihydrobenzo-dioxinyl,dioxo-tetrahydro-1H-benzo[e]diazepinyl, imidazopyridinyl,benzotriazolyl, benzoimidazolyl, oxo-dihydro-benzoimidazolyl, indolyl,indazolyl, naphthyridinyl, quinolinyl, benzoimidazothiazolyl, pyridinyl,pyrimidinyl, pyrrolyl, triazolyl, thienyl, thiazolyl, tetrahydrofuranylor pyrrolidinyl; wherein said R₄ is optionally substituted one or moretimes with a substituent selected from halogen, methyl, ethyl,isopropyl, propoxyethyl, phenyl, benzoyl, difluoromethoxy, CF₃, CN,acetyl, methanesulfonyl, sulfamoyl, dimethylamino, N-formyl-methylamino,2-hydroxyethylamino, 2-methoxyethylamido, benzyloxymethyl,carboxyphenoxy, pyrazolyl, 3,5-dimethyl-pyrazolyl, imidazolyl,triazolyl, oxazolyl, pyridinyl, oxo-dihydro-pyridinyl,pyrimidinyl-methylamino, N-acetyl-piperidinyl, morpholinyl,morpholinylmethyl or 2-oxo-pyrrolidinyl; or a salt thereof or anenantiomer or a diastereomer thereof.
 2. The compound according to claim1, wherein R is methyl; R₂ is methyl or CF₃; R₁ and R₃ are hydrogen. 3.The compound according to claim 1, wherein R is methyl; R₁ is methyl orCF₃; R₂ and R₃ are hydrogen.
 4. The compound according to claim 1,wherein R₄ is phenyl or phenyl substituted with one or more groupsselected from fluorine, chlorine, methyl, isopropyl, propoxyethyl, CF₃,CN, difluoromethoxy, methanesulfonyl, sulfamoyl, dimethylamino,N-formyl-methylamino, carboxyphenoxy, oxo-dihydro-pyridinyl,pyrimidinyl-methylamino, pyrazolyl, 3,5-dimethyl-pyrazolyl, imidazolyl,triazolyl, oxazolyl, N-acetyl-piperidinyl, morpholinylmethyl or2-oxo-pyrrolidinyl.
 5. The compound according to claim 1, wherein R₄ isselected from benzofuranyl, dihydro-benzofuranyl,oxo-tetrahydro-benzofuranyl, benzodioxolyl, dihydrobenzo-dioxinyl,dioxo-tetrahydro-1H-benzo[e]diazepinyl or oxo-chromenyl, which isoptionally substituted one or more times with chlorine or methyl.
 6. Thecompound according to claim 1, wherein R₄ is selected fromdimethylaminomethyl, methanesulfonylmethyl, phenoxymethyl, vinylbenzene,ethynylbenzene or vinylpyridine, which is optionally substituted one ormore times with fluorine.
 7. The compound according to claim 1, whereinR₄ is pyridinyl or pyrimidinyl, which is optionally substituted one ormore times with chlorine, methyl, 2-hydroxyethylamino,2-methoxyethylamido, benzyloxymethyl or morpholinyl.
 8. The compoundaccording to claim 1, wherein R₄ is selected from imidazopyridinyl,benzotriazolyl, benzoimidazolyl, oxo-dihydro-benzoimidazolyl, indolyl,indazolyl, naphthyridinyl, quinolinyl or benzoimidazothiazolyl, which isoptionally substituted one or more times with fluorine, chlorine,methyl, isopropyl, or pyridinyl.
 9. The compound according to claim 1,wherein R₄ is selected from pyrrolyl, triazolyl, thienyl or thiazolyl,which is optionally substituted one or more times with methyl, phenyl,benzoyl or pyridinyl.
 10. The compound according to claim 1, wherein R₄is selected from tetrahydrofuranyl or pyrrolidinyl, which is optionallysubstituted one or more times with acetyl.
 11. The compound according toclaim 1 which is having the formula (II):

wherein R, R₁, R₂, R₃ and R₄ are as defined in claim
 1. 12. Apharmaceutical composition comprising a compound of formula (I):

wherein R, R₁, R₂ and R₃ are the same or different and independently ofeach other chosen from hydrogen, (C₁-C₄)alkyl or CF₃; R₄ is selectedfrom the group consisting of dimethylaminomethyl, methanesulfonylmethyl,phenoxymethyl, vinylbenzene, ethynylbenzene, vinylpyridine, phenyl,benzofuranyl, dihydro-benzofuranyl, oxo-tetrahydro-benzofuranyl,benzodioxolyl, oxo-chromenyl, dihydrobenzo-dioxinyl,dioxo-tetrahydro-1H-benzo[e]diazepinyl, imidazopyridinyl,benzotriazolyl, benzoimidazolyl, oxo-dihydro-benzoimidazolyl, indolyl,indazolyl, naphthyridinyl, quinolinyl, benzoimidazothiazolyl, pyridinyl,pyrimidinyl, pyrrolyl, triazolyl, thienyl, thiazolyl, tetrahydrofuranylor pyrrolidinyl; wherein said R₄ is optionally substituted one or moretimes with a substituent selected from halogen, methyl, ethyl,isopropyl, propoxyethyl, phenyl, benzoyl, difluoromethoxy, CF₃, CN,acetyl, methanesulfonyl, sulfamoyl, dimethylamino, N-formyl-methylamino,2-hydroxyethylamino, 2-methoxyethylamido, benzyloxymethyl,carboxyphenoxy, pyrazolyl, 3,5-dimethyl-pyrazolyl, imidazolyl,triazolyl, oxazolyl, pyridinyl, oxo-dihydro-pyridinyl,pyrimidinyl-methylamino, N-acetyl-piperidinyl, morpholinyl,morpholinylmethyl or 2-oxo-pyrrolidinyl; or a pharmaceuticallyacceptable salt thereof or an enantiomer or a diastereomer thereof incombination with at least one pharmaceutically acceptable excipient,diluent or a carrier.
 13. The composition according to claim 12, whereinR₄ is phenyl or phenyl substituted with one or more groups selected fromfluorine, chlorine, methyl, isopropyl, propoxyethyl, CF₃, CN,difluoromethoxy, methanesulfonyl, sulfamoyl, dimethylamino,N-formyl-methylamino, carboxyphenoxy, oxo-dihydro-pyridinyl,pyrimidinyl-methylamino, pyrazolyl, 3,5-dimethyl-pyrazolyl, imidazolyl,triazolyl, oxazolyl, N-acetyl-piperidinyl, morpholinylmethyl or2-oxo-pyrrolidinyl.
 14. The composition according to claim 12, whereinR₄ is selected from benzofuranyl, dihydro-benzofuranyl,oxo-tetrahydro-benzofuranyl, benzodioxolyl, dihydrobenzo-dioxinyl,dioxo-tetrahydro-1H-benzo[e]diazepinyl or oxo-chromenyl, which isoptionally substituted one or more times with chlorine or methyl. 15.The composition according to claim 12, wherein R₄ is pyridinyl orpyrimidinyl, which is optionally substituted one or more times withchlorine, methyl, 2-hydroxyethylamino, 2-methoxyethylamido,benzyloxymethyl or morpholinyl.
 16. The composition according to claim12, wherein the compound is having the formula (II):

wherein R, R₁, R₂, R₃ and R₄ are as defined in claim
 12. 17. A method ofinhibiting or relieving a disease in a patient, said disease selectedfrom the group consisting of a sleep related disorder selected from thegroup consisting of narcolepsy, circadian rhythm sleep disorder,obstructive sleep apnea, periodic limb movement and restless legsyndrome, excessive sleepiness and drowsiness due to medicationside-effect, dementia, Alzheimer's disease, multiple sclerosis,attention deficit hyperactivity disorder and depression, comprisingadministering to said patient a therapeutically effective amount of acompound of formula (I):

wherein R, R₁, R₂ and R₃ are the same or different and independently ofeach other chosen from hydrogen, (C₁-C₄)alkyl or CF₃; R₄ is selectedfrom the group consisting of dimethylaminomethyl, methanesulfonylmethyl,phenoxymethyl, vinylbenzene, ethynylbenzene, vinylpyridine, phenyl,benzofuranyl, dihydro-benzofuranyl, oxo-tetrahydro-benzofuranyl,benzodioxolyl, oxo-chromenyl, dihydrobenzo-dioxinyl,dioxo-tetrahydro-1H-benzo[e]diazepinyl, imidazopyridinyl,benzotriazolyl, benzoimidazolyl, oxo-dihydro-benzoimidazolyl, indolyl,indazolyl, naphthyridinyl, quinolinyl, benzoimidazothiazolyl, pyridinyl,pyrimidinyl, pyrrolyl, triazolyl, thienyl, thiazolyl, tetrahydrofuranylor pyrrolidinyl; wherein said R₄ is optionally substituted one or moretimes with a substituent selected from halogen, methyl, ethyl,isopropyl, propoxyethyl, phenyl, benzoyl, difluoromethoxy, CF₃, CN,acetyl, methanesulfonyl, sulfamoyl, dimethylamino, N-formyl-methylamino,2-hydroxyethylamino, 2-methoxyethylamido, benzyloxymethyl,carboxyphenoxy, pyrazolyl, 3,5-dimethyl-pyrazolyl, imidazolyl,triazolyl, oxazolyl, pyridinyl, oxo-dihydro-pyridinyl,pyrimidinyl-methylamino, N-acetyl-piperidinyl, morpholinyl,morpholinylmethyl or 2-oxo-pyrrolidinyl; or a pharmaceuticallyacceptable salt thereof or an enantiomer or a diastereomer thereof incombination with at least one pharmaceutically acceptable excipient,diluent or a carrier.
 18. The method according to claim 17, wherein thedisease is selected from the group consisting or narcolepsy, circadianrhythm sleep disorder, obstructive sleep apnea, periodic limb movementand restless leg syndrome, excessive sleepiness and drowsiness due tomediation side-effect.
 19. The method according to claim 17, wherein thesleep disorder is narcolepsy.
 20. The method according to claim 17,wherein the disease is Alzheimer's disease.
 21. The method according toclaim 17, wherein the disease is depression.
 22. The method according toclaim 17, wherein the disease is dementia.
 23. The method according toclaim 17, wherein R₄ is phenyl or phenyl substituted with one or moregroups selected from fluorine, chlorine, methyl, isopropyl,propoxyethyl, CF₃, CN, difluoromethoxy, methanesulfonyl, sulfamoyl,dimethylamino, N-formyl-methylamino, carboxyphenoxy,oxo-dihydro-pyridinyl, pyrimidinyl-methylamino, pyrazolyl,3,5-dimethyl-pyrazolyl, imidazolyl, triazolyl, oxazolyl,N-acetyl-piperidinyl, morpholinylmethyl or 2-oxo-pyrrolidinyl.
 24. Themethod according to claim 17, wherein the compound is having the formula(II):

wherein R, R₁, R₂, R₃ and R₄ are as defined in claim 17.